University of California, San Francisco Logo

University of California, San Francisco | About UCSF | Search UCSF | UCSF Medical Center

Immunopathogenesis
Immunopathogenesis of HIV Infection
transparent image
transparent image
transparent image
transparent image
HIV and the Intricate Relationship between Viral Pathogenesis and Immune Defenses
transparent image
transparent image
Acquisition of HIV Infection
transparent image
transparent image
Acute Infection
transparent image
transparent image
Viral Reservoirs
transparent image
transparent image
Immune Deficiency and Chronic Infection
transparent image
transparent image
transparent imageCD4+ T Cells
transparent image
transparent imageCD8+ T Cells
transparent image
transparent imageB Lymphocytes and Antibody Production
transparent image
transparent imageMonocytes and Macrophages
transparent image
transparent imageDendritic Cells
transparent image
transparent imageNatural Killer Cells
transparent image
transparent imageGamma-Delta T Cells
transparent image
Immune Activation and HIV Infection
transparent image
transparent image
Immune Response to HIV
transparent image
transparent image
Pathogenesis of Immune Deficiency in HIV Infection
transparent image
transparent image
transparent imageSequestration in Lymphoid Organs
transparent image
transparent imageHeightened Destruction
transparent image
transparent imageDiminished Production
transparent image
Predictors of Immune Deterioration in HIV Infection
transparent image
transparent image
A Model for the Immunopathogenesis of HIV-Induced Immune Deficiency
transparent image
transparent image
transparent image
References
transparent image
transparent image
transparent image
transparent image
HIV and the Intricate Relationship between Viral Pathogenesis and Immune Defenses
transparent image

As intracellular parasites, all viruses must be intimately familiar with host cellular machinery and capable of suborning it to support their replication cycle. For HIV, this relationship is particularly complex and intimate because HIV targets, infects, and incapacitates cells central to antimicrobial defenses. Thus, host immune defenses and HIV pathogenesis are inextricably linked. Whereas this parasitic relationship may contribute to the persistence and progression of HIV infection, careful study of the relationship between HIV and the immune system has also yielded important insights into mechanisms of immune homeostasis and host defenses in general. This chapter will examine briefly the proposed mechanisms whereby HIV infects host immune cells, the mechanisms whereby host defenses are mobilized to attenuate HIV replication, the strategies HIV uses to evade host immune responses, and finally, the mechanisms whereby HIV induces immune deficiency that places persons at risk for the opportunistic infections and malignancies that define AIDS.

transparent image
Acquisition of HIV Infection
transparent image

In most infectious diseases, a number of factors contribute to the risk of acquisition of infection and to the occurrence of illness after exposure to a pathogenic organism. These include the nature of the exposure (eg, the route, the size of the microbial inoculum), the "virulence" of the microbe, and the nature of the host susceptibility to infection. The nature of the exposure clearly determines the risks of infection. Parenteral exposure to blood infected with HIV carries a substantial risk of infection. Among individuals transfused with blood of HIV-infected persons before screening of blood donors was practiced, the risk of infection approached 100%.(1) Transmucosal infection risks vary according to the site of exposure, with risks of transmission through rectal exposure exceeding the risks of transmission through vaginal exposure and both of the above exceeding the risks of transmission across oral mucosa. Mucosal inflammatory disease tends to enhance the risk of transmission particularly if associated with ulceration. Though firm data are lacking, epidemiologic evidence of seroconversion after accidental needlestick injuries (2) or sexual contact with infected persons with different levels of plasma HIV RNA suggest that the magnitude of the inoculum also contributes to the risk of infection.(3,4) Similarly, mother-to-infant transmission of HIV is enhanced among women with high levels of plasma HIV RNA, even after taking into account other known predictors of transmission,(5-7) and the intensity of exposure to contaminated antihemophilic factor concentrates has been shown to predict the risk of HIV infection among hemophiliacs.(8) Insight gained from persons at high risk for infection yet who persistently remain seronegative indicates that certain genetic loci can dramatically affect risk for acquisition of HIV infection. Specifically, persons homozygous for a 32-base-pair deletion (the so-called delta-32 mutation) in the C-C motif chemokine receptor 5 (CCR5) open reading frame that results in failure of surface expression of this key viral coreceptor are protected from acquisition of HIV infection.(9-11) In the rare instances when such persons have been found to be infected, they appear to acquire infection with viruses that may be capable of entry using the CXC motif chemokine receptor 4 (CXCR4) coreceptor.(12-14) In addition, persons with the -2459G polymorphism in the CCR5 promoter that may result in diminished CCR5 expression also may have a somewhat lower risk of infection than do persons with the alternative -2459A nucleotide at this site.(15) One other rare polymorphism in the CCR5 gene, characterized by a point mutation at position 303, introduces a premature stop codon in the elongating product chain and prevents the expression of a functional CCR5 coreceptor when associated with the delta-32 deletion, also conferring virtually complete resistance to CCR5-using viruses.(16)

As these studies have been performed among groups at risk for infection by both parenteral and mucosal routes, these observations suggest that acquisition of infection is highly dependent upon expression of the HIV coreceptor CCR5. The location of this critical "bottleneck" that requires CCR5 expression remains to be determined. One model proposes that CCR5-receptor availability is critical at the level of the mucosal dendritic (Langerhans) cells, which express CCR5 but much less CXCR4 or other C-type lectin receptors to which HIV may bind to facilitate cellular entry. On the other hand, a nonmucosal location for this bottleneck is suggested by the high prevalence of the CCR5 delta-32 homozygous state among seronegative hemophiliacs who otherwise appear to be at high risk for parenteral acquisition of infection.(17) Importantly however, among HIV seronegative cohorts at very high risk of either parenteral or transmucosal infection, only a minority (eg, 16% in a group of hemophiliacs at >95% risk of infection according to treatment history) are homozygous for the delta-32 mutation,(17) indicating that other mechanisms determine risks for and protection from HIV infection in these settings. Of note, members of several high-risk, HIV-seronegative cohorts have demonstrated immunologic "memory" of HIV exposure. Specifically, mucosal immunoglobulin A (IgA) capable of cross-clade HIV binding and neutralization has been found in genital secretions of some high-risk uninfected persons,(18) and low levels of CD8+ T cells reactive to HIV peptides have been found in circulation in other groups of high-risk seronegative individuals.(19,20) It is not yet clear whether these immune defenses are actually responsible for protection against infection or, alternatively, are a reflection only of exposure while protection is mediated by some other mechanisms that remain to be defined.

transparent image
Acute Infection
transparent image

Acute infection with HIV is often associated with a febrile illness and clinical evidence of systemic dissemination of virus to lymphoid tissue, the central nervous system, and other sites. High-level viral replication is reflected in high concentrations of virus in plasma and in lymphoid tissue. Viral replication characteristically peaks and then falls concurrently with the appearance in circulation of virus-specific CD8+ cytotoxic T cells.(21,22) As is the case in numerous other viral infections, these cytotoxic T lymphocytes are able to lyse infected host cells and likely attenuate the magnitude of HIV replication. Although animal models have established the importance of CD8+ cells in control of replication with the related simian immunodeficiency virus (SIV),(23,24) it has been very difficult to establish with certainty the nature of the CD8+ T-cell response that determines optimal control of HIV replication (see "Immune Response to HIV" below). Within several months after acquisition of infection, and in the absence of antiviral therapy, a "steady-state" level of HIV replication is established. This level tends to remain relatively stable for many years in a given individual but can vary enormously from person to person. A number of factors may determine steady-state HIV replication levels and these likely include the nature of host adaptive immune defenses, heterogeneities in viral replicative capacity, and heterogeneities in intrinsic host factors that may affect the magnitude of viral propagation.

Antibodies reactive with HIV antigens appear in circulation within a few weeks of infection but generally are first detectable after viral levels have begun to fall to the steady-state level. Although these antibodies often have strong neutralizing activity against the infecting virus, rapid viral escape from neutralization is characteristic, reflecting the enormous adaptability of the viral envelope, including its ability to revise its glycosylation sites, resulting in altered 3-dimensional configuration sufficient to escape antibody-mediated neutralization.(25)

transparent image
Viral Reservoirs
transparent image

Whereas most HIV replication is thought to take place in activated CD4+ T lymphocytes in lymphoid tissue, other cell populations may become infected and may play important roles in the persistence of HIV infection. Resting T cells constitute a significant reservoir of latent HIV that may be activated to complete the replication cycle upon activation of the host cell. At one end of the spectrum, in the activated T cell, multiple cellular factors and the viral Tat protein upregulate HIV transcription, resulting in viral production and ultimately destruction of the host cell.(26) At the other end of the spectrum, fully quiescent T cells, ie, those in the G0 phase of the cell cycle, are incapable of sustaining productive HIV replication, due to blocks in reverse transcription (27) as well as inability to enter the nucleus of the resting cell. Recent evidence indicates that, between those extremes, quiescent cells can be induced by exposure to certain cytokines to move far enough along the cell cycle (ie, to the G1 phase) to remove barriers to reverse transcription. Such cells are therefore susceptible to infection by HIV, but do not undergo full activation and cell cycling.(28) It is thought that these cells subsequently return to the fully quiescent state, in which they are protected from the cytopathic effects of massive viral replication. Infection of quiescent cells thus may establish a repository of infected cells capable of maintaining HIV for many years. How this takes place is not entirely clear but recent studies implicate the role of the HIV Nef protein as inducing a chain of events that renders resting CD4+ T cells susceptible to HIV infection.(29)

It has been shown in vivo that HIV can infect T cells that are not fully activated. During the course of HIV infection, integrated and infection-competent provirus can be found in a population of resting memory CD4+ T cells (30,31) and the frequency of these cells tends to remain stable for years, decreasing only minimally with the administration of combination antiretroviral therapies.(32,33)

Other proposed potential reservoirs of infection include sites within the genitourinary tract (34,35) and certain populations of monocytes and tissue macrophages,(36-38) particularly those in the central nervous system (39) and possibly the kidney.(40) In the resting memory cell compartment, sequence analysis has provided evidence of some replenishment of this reservoir over time. The relative stability and long half-life of these cells indicates that current treatment strategies likely will not be capable of eradication of infection in this compartment.(41) Neither intensive and prolonged administration of antiretroviral therapies (33,41) nor the design of strategies to activate expression of virus from these reservoirs by activating T cells through the T-cell receptor (TCR) or with IL-2 has been able to eradicate virus in infected persons, although the frequency with which virus can be found in resting memory cells has been modestly diminished by these therapies.(42,43) Moreover, mathematical modeling and limited experimental evidence suggest that pharmacologically induced, high-level T-cell stimulation not only is unlikely to eliminate the latent reservoir, but also could potentially lead to T-cell depletion and disrupt CD4/CD8 T-cell homeostasis.(44) Several excellent reviews of the role of cellular reservoirs in the pathogenesis of HIV infection have been published recently.(45-48)

transparent image
Immune Deficiency and Chronic Infection
transparent image

Although the precise mechanisms of immune dysfunction remain incompletely understood, virtually every arm of the immune response may be affected by HIV infection.

transparent image
CD4+ T Cells
transparent image

Progressive depletion in numbers of circulating CD4+ T cells occurs in almost all cases of untreated HIV infection. The number of circulating CD4+ T cells is widely used as a measure of global "immune competence" and provides a predictor of the immediate risk for opportunistic illnesses.(49) Earlier in the course of infection, many HIV-infected persons have a syndrome of generalized lymphadenopathy characterized by accumulation of lymphocytes within inflammatory lymph nodes and upregulation of adhesion molecule expression. Early in the course of infection, memory CD4+ T cells are selectively depleted from circulation; as disease advances, CD4+ T cells of both the naive and memory phenotype are lost from circulation.(50) In advanced disease, all CD4 cell populations are depleted from circulation and from lymphoid tissue sites.

Functional abnormalities of CD4+ T cells are also characteristic of progressive HIV infection. Failure of CD4+ lymphocytes to undergo cell division, for example, has been demonstrated following stimulation of T cells from infected individuals with antigens or mitogens in vitro. A sequential loss of immune responsiveness to recall antigens, followed by alloantigens and then mitogens has been described.(51) Diminished expression of IL-2 is readily demonstrable (51,52) in cells from HIV-infected individuals and may be related to the proliferation defects. In contrast, expression of interferon-gamma by these cells is often unimpaired,(52) suggesting that the defective responsiveness is not a consequence of depletion of antigen-reactive cells but rather a selective impairment in the ability of these cells to respond after engagement of TCRs. The function of CD4+ T cells that specifically recognize antigens from HIV itself appears to be selectively impaired early in the course of HIV infection (see "Immune Response to HIV" below).

Using anti-TCR antibody stimulation to characterize proliferation defects in CD4+ T cells indicates that proliferation defects in HIV disease are associated with early G1-phase cell-cycle arrest (53) and are more commonly observed in persons who have experienced sustained CD4 cell losses.(54) As a key role of CD4+ T cells is to facilitate immune responses though production of immunomodulatory cytokines, the loss of these cells and the failure of remaining cells to function properly constitutes a critical impairment in immune capability. Specific CD4+ T-cell responses to HIV antigens appear to be selectively and lastingly impaired during early HIV infection (see "Immune Response to HIV" below).

transparent image
CD8+ T Cells
transparent image

In early HIV infection, CD8+ T-cell numbers tend to increase, reflecting expansion of memory CD8+ T cells, particularly HIV-reactive cells. CD8 cell expansions persist until far advanced stages of HIV disease, when all T-cell numbers tend to fall.(55) In contrast to memory CD8 cell expansions, proportions of naive CD8 cells tend to fall in early infection, but absolute numbers of these cells do not fall until HIV disease progresses.(50) For example, in earlier disease CD8+ T cells that recognize cytomegalovirus are present in large numbers, but in advanced disease the cytolytic function of CD8+ T cells directed against opportunistic pathogens is demonstrably impaired.(56) It is not entirely clear whether the CD8+ cells present in early disease are functionally "normal," as the maturation phenotype of CD8+ T cells recognizing pathogen-derived peptides has been found to be variably perturbed.(57) Whether this is the cause or the consequence (or the interaction of both) of greater exposure to opportunistic pathogen-derived antigens in HIV-infected immunosuppressed persons is difficult to sort out.

As is seen with CD4+ T cells in HIV infection, CD8+ T cells obtained from HIV-infected persons may fail to proliferate in response to TCR activation in vitro.(58) In this setting, however, it is not clear whether the failure to proliferate is a consequence of failure of CD4+ T-cell help (via provision of IL-2 that is essential for CD8+ T-cell proliferation), a reflection of an intrinsic failure of CD8+ T-cell function, or a consequence of CD8+ T-cell maturation to a predominantly effector phenotype.

transparent image
B Lymphocytes and Antibody Production
transparent image

As with cellular immune responses, the humoral immune system in HIV infection is characterized by paradoxical hyperactivation and hyporesponsiveness. Hyperactivation is reflected in dramatic polyclonal hyperglobulinemia, only a portion of which is directed against HIV antigens;(59) bone marrow plasmacytosis;(60) heightened expression of activation molecules on circulating B lymphocytes;(61,62) the presence of autoreactive antibodies in plasma;(59,63) and instances of clinical autoimmunelike disease. B-cell hyperreactivity may contribute to the increased risk of B-cell lymphomas in HIV-infected persons, but no causal link has been clearly established.(64) Neither is the etiology of hyperglobulinemia well understood. Elevated plasma levels of the endogenous B-lymphocyte stimulator have been found in HIV-infected persons (65,66) and this may contribute to the B-lymphocyte activation of HIV infection and AIDS. At the same time, diminished B-lymphocyte responsiveness to antigenic stimulation in vitro is characteristic of HIV-infected persons,(62,67-69) who often fail to develop protective antibody responses after immunization with protein or with polysaccharide vaccines.(70-73) The characterization of antibody responses to polysaccharides as "T-cell independent" is only partially correct. Although antibodies can be induced to polysaccharides in the absence of linked peptides that induce cognate help by proximate CD4+ T cells, these responses are not optimal. Moreover, B-lymphocyte responses to pure sugars still require some degree of T-helper support. Lack of CD4 help may therefore underlie the poor antibody responses to polysaccharides that are seen in HIV infection.

transparent image
Monocytes and Macrophages
transparent image

Tissue macrophages are often infected with HIV in vivo (74-77) and, because they are generally not killed by the virus, may serve as reservoirs for viral replication. In tissue sites, infected macrophages may be the source not only of viral proteins but also of inflammatory mediators of pathology such as proinflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, and IL-10, as well as chemotactic chemokines. Circulating monocytes on the other hand seldom have been shown to harbor infectious HIV; moreover, in vitro studies of blood monocytes largely have failed to show substantial HIV-induced impairments in key functions such as antigen presentation and differentiation.(78,79) On the other hand, in vitro infection of monocyte-derived macrophages with HIV dramatically impairs the ability of these cells to ingest and kill foreign microbes (80,81) as well as to present antigen to T cells.(82) These findings suggest that impaired function of these infected cells in vivo may well contribute to the overall immune dysfunction of HIV infection.

transparent image
Dendritic Cells
transparent image

Characterized by large, dendritic cytoplasmic extensions, dendritic cells normally engage in efficient presentation of antigens to T and B lymphocytes in lymph nodes. Epidermal dendritic cells (Langerhans cells), characterized by expression of CD1a and Birbeck granules, may be among the first cells to encounter HIV at mucosal surfaces and, in the course of transporting antigens encountered at epidermal sites, have the capability of transporting HIV to lymphoid tissue. Two populations of dendritic cells can be identified in blood: myeloid dendritic cells (characterized by expression of CD11c) and plasmacytoid dendritic cells (CD123+). Circulating numbers of these cells tend to be diminished in HIV infection.(83-86) Recent studies suggest that there are decreases in both number and function of circulating dendritic cells in HIV-infected persons and that the decreases are not normalized with suppression of HIV replication.(87) The ability of these cells to mature remains incompletely determined. Studies of these cells are hampered by their relative scarcity, as they generally account for <1% of circulating mononuclear cells. The plasmacytoid dendritic cell is a major producer of interferon-alfa and a small but growing body of literature suggests that preservation of these cells in advanced HIV infection is associated with fewer severe opportunistic complications.(88,89)

The follicular dendritic cell found in lymphoid tissue is also a key antigen-presenting cell that traps and maintains intact antigens on its cell surface. In untreated HIV infection, the surface of this cell is often loaded with virus and viral antigen. In the lymph node follicles, this cell provides key signals for the activation of B lymphocytes. The follicular dendritic cell is related to the other dendritic cells discussed above only in terms of its dendritic morphology; the origin of this cell is not well understood.

transparent image
Natural Killer Cells
transparent image

Natural killer cells are large granular lymphocytes with cytolytic capabilities. Lytic activity is greatest against tumor cells and virus-infected cells that have diminished expression of major histocompatibility complex (MHC) class I antigens. Because MHC class I expression is required for peptide presentation to T-cell receptors, natural killer cells comprise a cellular component of the innate host defense system with activity against cells that may escape adaptive host defenses because of failure of MHC class I expression. Lysis by natural killer cells also can be directed against cells recognized by host antibodies through binding of immunoglobulin to fragment constant receptors on the natural killer cell. Thus, natural killer cells contribute to both innate and adaptive immune host defenses. Early studies have demonstrated impairments in natural killer cell activity in persons with AIDS and HIV infection,(90,91) and functional impairments of these cells have been attributed to a failure of the postbinding lytic event.(92) Some of this impairment is correctible in vitro after overnight cultivation in medium or after addition of the helper-cell-derived cytokines IL-2 or interferon-gamma,(90,93) suggesting that "exhaustion" and/or failure of CD4 cell help may underlie this defect.

transparent image
Gamma-Delta T Cells
transparent image

These infrequent cells (comprising between 1% and 5% of the T-lymphocyte pool) are cells that may, as do natural killer cells, play roles in both innate and adaptive immune responses. The antigen-binding sites of T-cell receptors of these lymphocytes are comprised of gamma and delta heterodimers as contrasted with the alpha and beta chains of most T lymphocytes. These T cells can recognize microbial antigens directly without processing and presentation on host human leukocyte antigen (HLA) molecules. Although the genes encoding these receptor chains also undergo rearrangement, the diversity of these receptors is more restricted than that of T cells with alpha-beta chain receptors. The cytokinetic and cytolytic functions of cytokinetic are often perturbed, whereas proliferation responses are variably affected in HIV infection.(94-96)

transparent image
Immune Activation and HIV Infection
transparent image

It has long been recognized that infection with HIV is characterized not only by development of profound immunodeficiency but also by sustained and dramatic immune activation.(97,98) In fact, a growing body of evidence establishes immune activation as a critical underlying mediator of immune dysfunction and immune deficiency.(99-101) This state of immune activation is manifested both by enhanced expression of phenotypic activation markers on peripheral blood T cells and B cells and by increased plasma levels of inflammatory cytokines; moreover, lymphocytes obtained from HIV-infected persons are more often found in activated phases of the cell cycle.

In HIV-infected subjects, T lymphocytes often express surface markers of immune activation such as HLA class II molecules and CD38, a membrane-bound adenosine 5'-diphosphate (ADP) ribosyl cyclase.(102,103) These markers of activation are elevated in direct proportion to the magnitude of HIV replication (104,105) and some studies have found that the extent of CD38 expression predicts ultimate HIV disease course more accurately than do plasma levels of HIV itself.(104,106) Although a simple explanation for this state of persistent immune activation would be a reflection of HIV-specific T-cell expansion, the frequency of phenotypically activated CD8+ T cells found in HIV-infected subjects is often greater than 80%,(101) substantially exceeding the proportion of cells that can be shown to recognize HIV peptides.(107)

Thus, a significant proportion of this activation may represent a response to other antigens, or may be an indirect (or bystander) effect of HIV replication. In HIV infection, T cells are also more extensively primed to enter the replication phases of the cell cycle. This propensity is evidenced by an increased frequency both of cells expressing the nuclear antigen Ki67 (101,108) and of cells exhibiting increased DNA content and 5-bromo-2'-deoxyuridine (BrdU) incorporation, a reflection of spontaneous progression to the synthesis phase of the cell cycle.(109,110)

Plasma levels of TNF-alpha, IL-1, and IL-6 are often elevated in later stages of HIV infection, and both TNF and IL-6 levels also are directly correlated with plasma HIV RNA levels.(111) Interestingly, in lymphoid tissue, the primary site of HIV replication, levels of TNF-alpha are not generally increased, although expression of IL-1, IL-2, IL-6, IL-12, and interferon-gamma may be elevated.(112)

With administration of antiretroviral therapies, these indices of immune activation tend to fall, indicating that HIV replication induces the state of high-level activation.(113-117) The plausible hypothesis that HIV-induced activation enhances the magnitude of HIV replication by increasing the numbers of cells susceptible to and supportive of productive viral replication remains unproven. In this regard, it should be noted that expression of CD38 may limit the susceptibility of cells to productive HIV replication.(118)

Animal studies support the relationship between immune activation and progressive cellular immune deficiency. A natural host of SIV, the sooty mangabey permits high-level SIV replication but manifests limited evidence of disease.(119) Strikingly, this lack of pathogenicity is accompanied by absence of the extensive immune activation and cellular proliferation that characterizes SIV infection of other primates such as the rhesus macaque, in which immune activation closely mimics the activation seen in HIV-infected humans.(120) Moreover, mangabeys seem to maintain thymic and bone marrow function and do not demonstrate so-called bystander lymphocyte apoptosis,(121) whereby uninfected cells in the vicinity of an infected cell are induced to undergo programmed cell death. Finally, in a preliminary human study, blocking immune activation by administration of the immune suppressant cyclosporine A concomitantly with initiation of combination antiretroviral therapies resulted in more sustained CD4+ T-cell restoration than had been seen with antiviral therapies alone.(122)

transparent image
Immune Response to HIV
transparent image

As noted above, infection with HIV is associated with a brisk immune response to HIV antigens. Although antibody levels are high, neutralizing antibody responses against HIV are not strong, and are followed in rapid sequence by the emergence of viruses resistant to the neutralizing activity of these antibodies.(25) Thus, although these antibodies possess sufficient activity to exert selection pressure, the target epitopes are in regions that can readily sustain mutational escape (123) or can be shielded by mutations altering the numerous glycosylation sites on the viral envelope.(25)

Following initial infection with HIV, the rapid emergence of cytolytic T-cell responses, largely CD8+ T-cell responses, is associated temporally with a decrease in plasma levels of HIV.(21) CD8+ T cells may help control HIV replication in several ways. First, binding of these cells to viral peptides presented by HLAs on the surface of infected cells can trigger a cytolytic response resulting in the destruction of the target cell that is producing virus. This function is largely mediated through the liberation of perforin, which generates a hole in the target cell through which granzymes can enter and destroy the cell before it can produce large numbers of progeny virions. Although most cytolytic activity against viral targets is mediated through this route, CD8+ T cells expressing Fas ligand also can bind to Fas (CD95) on the surface of target cells, thereby inducing apoptotic cell death. Finally, CD8+ T cells can liberate a number of soluble factors with antiviral activity. These include interferon-gamma, which can, via a complex cascade of receptor-mediated binding and activation, render nearby cells relatively resistant to productive viral infection. CD8+ T cells also are sources of the beta chemokines MIP-1a (macrophage inflammatory protein-1 alpha), MIP-1b (macrophage inflammatory protein-1 beta), and RANTES (regulated on activation, normal T expressed and secreted), which bind to CCR5 and, by promoting internalization of this critical HIV coreceptor, decrease the ability of HIV to gain entry into otherwise susceptible cells.(124) A number of other antiviral factors also can be expressed by CD8+ T cells and these may include an incompletely described "cell antiviral factor" (CAF) (125) that blocks HIV replication largely via inhibition of viral transcriptional activation.(126) The precise definition of CAF is not available although CAF activity does appear to be distinguishable from chemokine-mediated (127,128) or defensin-mediated (129) suppression of HIV. CD8-mediated suppression of HIV may be related to disease outcome since this cellular response is augmented by supernatants prepared from cells from long-term nonprogressors (persons with stable CD4 cell counts and sustained low levels of HIV replication in the absence of antiretroviral treatment).(130-133) It is difficult to determine whether these factors and activities actually cause a better disease outcome or whether they are merely reflections of better preservation of host defenses.

Whereas it is clear from both human and animal models that CD8+ T cells are important in control of retroviral replication, it is not entirely clear what, if any, kind of CD8+ T-cell response can confer sustained control of HIV replication. Nor is it clear whether or not the magnitude or the breadth of CD8+ T-cell target recognition reliably predicts disease course.(134,135)

Despite relatively high frequencies of HIV-specific CD8+ T cells in HIV-infected individuals,(134,136-138) sustained suppression of viral replication is rarely achieved. The emergence of viral escape mutations that render virus-infected cells undetectable by host cytotoxic T-lymphocyte assay may help to explain this observation.(139,140) Moreover, there is some evidence that HIV-specific CD8+ T cells may be dysfunctional, as indicated by reduced lytic activity,(141,142) poor proliferation function in vitro,(58) and decreased expression of key signaling molecules (143) that mediate TCR activation. Whether this is a consequence of sustained exposure to high levels of viral antigen or is related to the lack of CD4 help or direct exposure to toxic viral products and the effects of chronic inflammation remains to be determined.

Importantly, CD4+ T-cell responses to HIV antigens are dysregulated in HIV infection, to an extent that exceeds the impairment of responses to other microbial antigens.(103,144,145) Although interferon-gamma expression is readily induced in response to HIV antigens even in advanced disease,(146) CD4 T-cell proliferation is rarely detected in untreated infection except among long-term nonprogressors.(147) CD4+ T-cell proliferation responses to HIV antigens sometimes can be preserved or restored in HIV-infected persons who are treated shortly after acquisition of infection (148) and in a proportion of chronically infected persons in whom viral replication is suppressed by antiretroviral therapies.(149,150) Importantly, restoration of these responses is less common in persons who begin suppressive antiretroviral therapy with moderately advanced or advanced infection.(103,151)

Thus, CD4+ T-cell responses to HIV antigens appear to be selectively impaired during high-level viremia and may be restored when HIV replication is brought under control by therapy.(149,152) Although HIV-reactive CD4+ T cells are preferentially susceptible to HIV infection,(153) it is not likely that this phenomenon is sufficient to explain the impaired proliferation responses seen during uncontrolled HIV replication. For example, the persistence of HIV-specific interferon-gamma responses even in persons with advanced disease (146) suggests that the ability of HIV-specific CD4 cells to expand may be selectively impaired while other HIV-specific immune functions (such as interferon production) may be preserved. Conceivably, HIV-reactive cells potentially capable of proliferation are selectively targeted and destroyed, or their replication capacity is impaired in the setting of viral activity. Sustained and relatively selective infection of HIV-reactive CD4+ cells may underlie the failure to restore CD4+ T-cell proliferation responses when persons with advanced disease initiate treatment with antiretroviral therapy.

transparent image
Pathogenesis of Immune Deficiency in HIV Infection
transparent image

The characteristic depletion of CD4+ T lymphocytes in HIV disease appears to result from factors other than the direct cytopathic effect of HIV itself. Cellular destruction, diminished cellular production, and cellular sequestration all appear to contribute to decreases in numbers of circulating CD4+ T cells.

transparent image
Sequestration in Lymphoid Organs
transparent image

Much of the immune damage that is seen in HIV infection probably results from viral replication and its consequences in lymphoid tissue. In early stages of HIV infection, generalized lymphadenopathy is commonly recognized.(154,155) In this condition, nodes are filled with lymphocytes, and the representation of CD4+ and CD8+ T lymphocytes in these sites is generally reflective of what is seen in circulation.(156) In untreated HIV infection, lymph nodes show inflammation with heightened expression of cytokines such as interferon-gamma, IL-1, IL-2, and IL-12.(157-160) The inflammatory condition of the lymphoid tissues likely is a consequence of high-level HIV replication at these sites. These inflammatory lymph nodes are also characterized by heightened expression of molecules such as intercellular adhesion molecules and vascular cell adhesion molecules.(161) This "sticky" and inflammatory state likely results in sequestration of circulating lymphocytes in these sites. As disease advances, there is progressive destruction of lymphoid architecture (162) and ultimately lymphoid tissues are, as is the circulation, depleted of lymphocytes.

transparent image
Heightened Destruction
transparent image

As noted above, the immune deficiency of HIV infection is characterized by immune activation, with an increased frequency of circulating lymphocytes that have been activated to enter the cell cycle. Interestingly, this heightened entry to the cell cycle is often aborted (at least after in vitro cultivation) as the activated cells tend to die by mechanisms of programmed cell death (109) and also, in some studies, by necrotic cell death.(163,164) This may be true especially for CD4+ T cells, in which studies of telomere length fail to show evidence of sustained successful division (165) despite evidence of heightened cellular proliferation and turnover in vivo (166,167) or ex vitro.(168,169) In contrast, though CD8+ T cells in HIV infection also die after activation,(170) CD8+ T-cell populations in HIV infection tend to have shortening of the average telomere length reflective of multiple rounds of successful cellular replication (at least among the surviving cells).(165) Importantly, for CD4+ T cells, the proportion of cells that are activated, the proportion of cells that incorporate label into DNA, and the proportion of cells that can be demonstrated to die via apoptosis ex vivo far exceed the proportion of cells that are demonstrably infected by HIV; the same can be said for CD8+ T cells, which are rarely infected in vivo. Although antigenic stimulation in response to peptide antigens of HIV itself may account for some portion of the observed activation, the proportion of CD8 cells activated to express activation markers (either CD38 or HLA-DR) far exceeds the proportion of cells recognized to be HIV reactive;(107) the same appears to be true for CD4+ T cells (171) although screening for CD4 cell reactivity has been less comprehensive than has screening for CD8 cell reactivity. Therefore, cellular activation and cell death in HIV infection appear to be entirely determined neither by direct cytopathic effects of the virus nor by immune activation driven by specific peptide recognition. Alternative explanations, such as dysregulated activation of T cells though mechanisms other than T-cell receptor activation, are yet unproven.

transparent image
Diminished Production
transparent image

Whereas HIV infection clearly is characterized by heightened cellular destruction and turnover, there is also evidence that immune cellular production may be impaired, at least at certain stages of infection. With advancing stages of HIV infection, there is evidence of cellular hypoproductivity in bone marrow. Pancytopenia is not uncommon in advanced AIDS and bone marrow biopsies often reveal evidence of hypoplasia. Moreover, CD34+ hematopoietic progenitor cells in bone marrow appear susceptible to infection with HIV (172) and impairment of the function of these cells has been described.(173,174) The mechanisms whereby bone marrow productivity is impaired in HIV disease are incompletely understood and it is likely that concurrent infection with opportunistic pathogens such as cytomegalovirus and Mycobacterium avium complex may contribute to this suppression in some persons. Nonetheless, with administration of suppressive antiretroviral therapies, peripheral blood cytopenias characteristically improve.(175)

T lymphocytes undergo maturation and rearrangement of T-cell receptor genes in the thymus, where T cells with receptors of very high avidity for host HLAs that bind endogenous peptides are deleted (this prevents too much autoimmune reactivity) as are T cells with very low avidity for the host HLAs (this assures that remaining T cells are potentially capable of recognizing host HLAs that bind foreign peptides). The population of antigen-naive T lymphocytes that emerges contains a diverse distribution of T-cell receptors with specificities capable of recognizing a broad array of peptide antigens bound to the host's own cell-surface HLAs. Although thymic activity is greatest during development and childhood, there is evidence of thymic function in adulthood as well.(176,177) The role of the thymus in HIV disease is complex. Thymus size is often preserved in HIV-infected adults (particularly in older persons) (178,179) and there is indication that thymic output often is maintained in infected persons.(180) Moreover, preliminary data indicate that in some persons with HIV infection, thymic size is actually diminished after suppression of HIV replication,(181) suggesting that in some HIV-infected persons, thymic function (or thymic size at least) increases during uncontrolled HIV replication, perhaps in order to keep up with the increased demands of HIV-induced cellular turnover, and that this demand falls as HIV replication and immune cell destruction are diminished by antiretroviral therapies. However, there is also evidence that HIV can infect thymic stromal cells and that HIV strains capable of using the CXCR4 coreceptor (X4 strains) can infect thymocytes as well.(182) Moreover, there is clear evidence of thymic failure among persons who fail to increase circulating CD4 cell numbers with antiretroviral therapy-induced suppression of HIV replication.(183)

IL-7 is a cytokine that may be important in thymopoiesis and in promoting naive T-cell expansion.(184-186) Circulating IL-7 levels are often elevated in HIV infection, particularly as CD4 cell counts fall below 100 cells/µL,(187,188) suggesting that increased levels of this cytokine may play an important role in driving T-cell production and homeostasis. Studies of IL-7 administration in SIV-infected macaques and in humans are ongoing and may help to elucidate a possible role for this agent in the treatment of HIV-associated immune deficiency.

transparent image
Predictors of Immune Deterioration in HIV Infection
transparent image

The rate of disease progression in untreated HIV infection is highly variable, with some individuals progressing rapidly to experience opportunistic infection and death within months of acquisition of infection and others (ie, long-term nonprogressors) remaining entirely well and maintaining normal CD4 cell counts more than 15 years after infection in the absence of antiretroviral treatment. (Approximately half of persons who acquire HIV infection will develop severe disease--AIDS--within 10 years if not treated with antiretroviral therapies.) Although long-term nonprogressors represent no more than about 5% of HIV-infected individuals, this variability suggests a need to identify the factors that determine rates of disease progression.

From a clinical perspective, rates of disease progression can be quantified by measuring decreases in circulating CD4 cell numbers over time. This index is highly variable among infected persons. A number of factors that predict the risk of disease progression, measured as rate of CD4 cell decline, progression to opportunistic infection or death, or risk of progression to CD4 cell counts of <200/µL, have been identified. Both viral factors and host factors, and likely their interaction, may predict the risk of HIV disease progression.

The magnitude of HIV replication as reflected in plasma HIV RNA levels is one predictor of the risk for HIV disease progression.(189) The relationship between the extent of HIV replication and disease progression, however, is complex and cannot be conceptualized in terms of a simple linear correlation between plasma HIV RNA level and rate of disease progression across all groups of HIV-infected individuals. For instance, disease progression is seen at significantly lower HIV RNA levels in women than in men.(190) In a limited number of cases, viral heterogeneities may explain differences in rates of disease progression. For example, in a small cohort of individuals who were infected by blood transfusion from a single donor in Australia and subsequently experienced a milder disease course than was expected, the infecting viral isolate was found to have a truncated Nef protein.(191,192) Other studies of HIV-infected persons with divergent disease progression rates have failed to identify plausible sequence or functional differences in the long-term repeat (LTR) and Tat sequences, (193,194) but do not rule out the possibility that heterogeneities in these viral sequences may have an impact on disease course.

Switches in envelope sequences resulting in a phenotype that utilizes the CXCR4 coreceptor are associated with evidence of accelerated HIV disease progression,(195) but the details of how coreceptor use determines disease outcome remain to be established.

The complex interplay between viral fitness and disease progression is potentially significant. Since replicative fitness correlates with plasma HIV RNA levels, more "fit" viruses might be expected to produce faster CD4 cell declines, as has been found to be the case in the context of antiviral drug resistance mutations. In the presence of antiviral drug selection pressure, resistance mutations either to nucleoside reverse transcriptase inhibitors (196,197) or to protease inhibitors (198,199) tend to attenuate the CD4 cell decline induced by wild-type virus. Although this effect may be due in part to diminished replicative capacity of these viruses, there is also reason to believe that decreased plasma HIV RNA levels do not completely explain the effect of fitness on CD4 cell levels and that the intrinsically diminished ability of these viruses to cause immunopathology also may play a role.(200,201)

Host genetic factors further determine the magnitude of HIV replication. For example, persons who are heterozygous for the delta-32 base pair deletion in the CCR5 open reading frame have decreased expression of cell-surface CCR5, lower HIV RNA levels, and slower disease progression.(202) Similarly, the G polymorphism in the -2459 sequence of the CCR5 promoter has been associated with decreased plasma HIV RNA levels and a modest decrease in risk of disease progression.(203) Peripheral blood and Langerhans cells obtained from persons with this genotype show diminished levels of HIV replication in vitro.(15,204) The -28G polymorphism in the promoter of the gene for the CCR5 ligand RANTES supports increased expression of RANTES and is associated with a decreased rate of CD4 decline in infected persons.(205) Another chemokine receptor gene polymorphism, the CCR2 64I allele, is also associated with a decreased risk of HIV disease progression.(203) However, as this receptor is not thought to be important in HIV infection, the mechanism for this effect (possible linkage to another genetic polymorphism) remains to be determined. Persons homozygous for a noncoding sequence in the gene for stromal cell-derived factor 1, the natural ligand for CXCR4, were found to have a delayed risk for progression to AIDS (206) but this observation has not been confirmed in other cohorts.(203)

Factors associated with adaptive immune responses to HIV are also indicators of disease progression risk. For example, certain HLA alleles indicate greater or lesser risks of disease progression.(207,208) In addition, viral mutations that impair binding of specific viral peptides to the HLA of a given patient predict higher levels of HIV replication.(209) Thus, the emergence of viral mutations at loci involved in HLA binding permits escape from protective immune defenses. In addition, homozygosity for HLA alleles is associated with a significantly greater risk of disease progression.(210) Because homozygosity (having fewer distinct HLA molecules) effectively decreases the diversity of peptide-HLA combinations available for recognition, potentially protective immune responses to HIV are limited. Finally, even a single amino acid substitution in an HLA molecule that determines which peptides can be bound and presented by this HLA type can determine a differential risk of HIV disease progression.(211) Thus, some degree of individual variation in HIV replication and ultimately in risk for disease progression is determined by HLA type and diversity.

Less is known about the innate immune responses that may limit HIV replication. Innate defenses are responsible for the most rapid responses to microbial invasion; they help to control microbial replication and to activate the more specific adaptive immune responses. A preliminary report suggests that the killer immunoglobulin-like receptor (KIR) allele KIR 3DS1, which activates natural killer cells, in the presence of the HLA-B BW4-80ILE allele, protects against disease progression in HIV infection,(212) suggesting that innate immune function is also important in the control of HIV disease. Additional studies indicate that preservation of the function and numbers of plasmacytoid dendritic cells--the major sources of interferon-alfa--is associated with protection of persons with advanced HIV disease from the occurrence of opportunistic infection.(88,89)

Nonspecific immune activation is a clear consequence of HIV infection and is correlated with increased HIV replication. For example, plasma concentrations of beta-2 microglobulin, TNF and its receptors, neopterin, and the soluble IL-2 receptor CD25 each correlate with magnitude of HIV replication and risk of disease progression.(213) Similarly, the expression of the activation marker CD38 on CD8 cells is correlated with HIV levels in plasma,(105) but in some studies independently adds predictive value for disease progression,(214,215) as does the level of CD38 expression on CD4+ T cells.(216) Moreover, levels of CD38 expression seem to exhibit an inverse linear correlation with the extent of CD4+ T-cell restoration in response to antiretroviral therapy.(217) Data from a cross-sectional study support a model wherein HIV replication drives immune activation that drives CD4 cell losses.(218)

Finally, age at the time of HIV infection also appears to be correlated with risk of disease progression. Data from large cooperative cohort studies indicate that the correlation of age with risk of disease progression and HIV-related mortality persists after adjusting for CD4 cell counts and plasma HIV RNA level.(219) Recent data comparing HIV-infected subjects to age-matched healthy controls suggest that the effect of age on the clinical course of HIV infection may be related to depletion of naive T cells, diminished CD28 expression, and reduced thymic volumes in older individuals.(179)

transparent image
A Model for the Immunopathogenesis of HIV-Induced Immune Deficiency
transparent image

As this chapter has shown, the interactions between HIV and the host response are complex and only partially characterized. Nonetheless, the existing data permit us to propose a model for the pathogenesis of immune deficiency in HIV infection. In this model, lymphoid sites of HIV replication serve as the major sites of immunopathology. At these inflammatory sites of viral replication, heightened adhesion molecule expression results in increased trapping of circulating lymphocytes, often reflected clinically as generalized lymphadenopathy. Trapped lymphocytes at these sites are exposed to a number of signals. Some of these signals may be driven by toxic viral products such as free envelope glycoprotein and viral regulatory proteins. Others may be mediated by cytokines induced at these sites during the intensive and sustained exposure to viral antigens or viral replication. Still other signals are driven by T-cell receptor engagement though binding of antigenic peptides. As a result of these events, both CD4 and CD8 T cells are activated in a dysregulated fashion, and activation may be both antigen-driven and antigen-independent (ie, not driven through T-cell receptor engagement). In this model, both antigen- and cytokine- or viral product-mediated T-cell activation induces cells to enter the cell cycle. The outcome of these events is not only heightened immune activation but also heightened cell death, because even physiologic cellular activation generally is accompanied by increased T-cell death.

It is proposed that both physiologic and dysregulated activation contribute to the profound immune activation and accelerated cell death that characterizes HIV infection. In early stages of infection, antigen-driven CD8+ T-cell expansion predominates, possibly because activated CD8+ T-cells are less susceptible than CD4+ T cells to productive and cytopathic HIV infection at lymphoid sites. Nonetheless, sustained exposure to this "toxic" milieu results in surviving CD4 and CD8 T-cell populations that are functionally impaired in their ability to mediate effector functions such as cytolysis, and are also impaired in the ability to expand in response to T-cell receptor engagement. The result is a less effective and less adaptable immune response to opportunistic pathogens. With advanced disease, bone marrow, the thymus, or both may fail to keep up with the heightened demand for cellular production, and severe immunodeficiency ensues. This model suggests that sustained exposure to viral replication results in immunologic impairments that are not readily reversible and that immune suppressive strategies may provide adjunctive value to antiviral therapies, and preliminary data suggest that this may indeed be the case.(54,122,220) Consistent with this, clinical responses to treatment with antiviral therapies are often less effective when treatment is begun at more advanced stages of disease.(221)

transparent image
transparent image

References

transparent image
1.   Msellati P, Dupon M, Morlat P, Lacoste D, Pellegrin JL, Dabis F. A cohort study of 89 HIV-1-infected adult patients contaminated by blood products: Bordeaux 1981-1989. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA). Aids 1990; 4:1105-9.
transparent image
2.   Cardo DM, Culver DH, Ciesielski CA, Srivastava PU, Marcus R, Abiteboul D, Heptonstall J, Ippolito G, Lot F, McKibben PS, Bell DM. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med 1997; 337:1485-90.
transparent image
3.   Pedraza MA, del Romero J, Roldan F, Garcia S, Ayerbe MC, Noriega AR, Alcami J. Heterosexual transmission of HIV-1 is associated with high plasma viral load levels and a positive viral isolation in the infected partner. J Acquir Immune Defic Syndr 1999; 21:120-5.
transparent image
4.   Fideli US, Allen SA, Musonda R, Trask S, Hahn BH, Weiss H, Mulenga J, Kasolo F, Vermund SH, Aldrovandi GM. Virologic and immunologic determinants of heterosexual transmission of human immunodeficiency virus type 1 in Africa. AIDS Res Hum Retroviruses 2001; 17:901-10.
transparent image
5.   Mofenson LM, Lambert JS, Stiehm ER, Bethel J, Meyer WA, 3rd, Whitehouse J, Moye J, Jr., Reichelderfer P, Harris DR, Fowler MG, Mathieson BJ, Nemo GJ. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 1999; 341:385-93.
transparent image
6.   Garcia PM, Kalish LA, Pitt J, Minkoff H, Quinn TC, Burchett SK, Kornegay J, Jackson B, Moye J, Hanson C, Zorrilla C, Lew JF. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med 1999; 341:394-402.
transparent image
7.   Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, O'Sullivan MJ, Van Dyke RB, Jimenez E, Rouzioux C, Flynn PM, Sullivan JL. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1996; 335:1621-9.
transparent image
8.   Kroner BL, Rosenberg PS, Aledort LM, Alvord WG, Goedert JJ. HIV-1 infection incidence among persons with hemophilia in the United States and western Europe, 1978-1990. Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr 1994; 7:279-86.
transparent image
9.   Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 86:367-77.
transparent image
10.   Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G, Parmentier M. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382:722-5.
transparent image
11.   Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996; 273:1856-62.
transparent image
12.   Michael NL, Nelson JA, KewalRamani VN, Chang G, O'Brien SJ, Mascola JR, Volsky B, Louder M, White GC, 2nd, Littman DR, Swanstrom R, O'Brien TR. Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. J Virol 1998; 72:6040-7.
transparent image
13.   Iversen AK, Christiansen CB, Attermann J, Eugen-Olsen J, Schulman S, Berntorp E, Ingerslev J, Fugger L, Scheibel E, Tengborn L, Gerstoft J, Dickmeiss E, Svejgaard A, Skinhoj P. Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus. J Infect Dis 2003; 187:215-25.
transparent image
14.   Naif HM, Cunningham AL, Alali M, Li S, Nasr N, Buhler MM, Schols D, de Clercq E, Stewart G. A human immunodeficiency virus type 1 isolate from an infected person homozygous for CCR5Delta32 exhibits dual tropism by infecting macrophages and MT2 cells via CXCR4. J Virol 2002; 76:3114-24.
transparent image
15.   Kawamura T, Gulden FO, Sugaya M, McNamara DT, Borris DL, Lederman MM, Orenstein JM, Zimmerman PA, Blauvelt A. R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc Natl Acad Sci U S A 2003; 100:8401-6.
transparent image
16.   Quillent C, Oberlin E, Braun J, Rousset D, Gonzalez-Canali G, Metais P, Montagnier L, Virelizier JL, Arenzana-Seisdedos F, Beretta A. HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene. Lancet 1998; 351:14-8.
transparent image
17.   Salkowitz JR, Purvis SF, Meyerson H, Zimmerman P, O'Brien TR, Aledort L, Eyster ME, Hilgartner M, Kessler C, Konkle BA, White GC, 2nd, Goedert JJ, Lederman MM. Characterization of high-risk HIV-1 seronegative hemophiliacs. Clin Immunol 2001; 98:200-11.
transparent image
18.   Devito C, Hinkula J, Kaul R, Kimani J, Kiama P, Lopalco L, Barass C, Piconi S, Trabattoni D, Bwayo JJ, Plummer F, Clerici M, Broliden K. Cross-clade HIV-1-specific neutralizing IgA in mucosal and systemic compartments of HIV-1-exposed, persistently seronegative subjects. J Acquir Immune Defic Syndr 2002; 30:413-20.
transparent image
19.   Bernard NF, Yannakis CM, Lee JS, Tsoukas CM. Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte activity in HIV-exposed seronegative persons. J Infect Dis 1999; 179:538-47.
transparent image
20.   Rowland-Jones S, Sutton J, Ariyoshi K, Dong T, Gotch F, McAdam S, Whitby D, Sabally S, Gallimore A, Corrah T, et al. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat Med 1995; 1:59-64.
transparent image
21.   Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68:4650-5.
transparent image
22.   Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283:857-60.
transparent image
23.   Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994; 68:6103-10.
transparent image
24.   Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, Kostrikis LG, Zhang L, Perelson AS, Ho DD. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999; 189:991-8.
transparent image
25.   Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, Salazar-Gonzalez JF, Salazar MG, Kilby JM, Saag MS, Komarova NL, Nowak MA, Hahn BH, Kwong PD, Shaw GM. Antibody neutralization and escape by HIV-1. Nature 2003; 422:307-12.
transparent image
26.   Stevenson M. HIV-1 pathogenesis. Nat Med 2003; 9:853-60.
transparent image
27.   Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. Embo J 1990; 9:1551-60.
transparent image
28.   Unutmaz D, KewalRamani VN, Marmon S, Littman DR. Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J Exp Med 1999; 189:1735-46.
transparent image
29.   Swingler S, Brichacek B, Jacque JM, Ulich C, Zhou J, Stevenson M. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature. 2003 Jul 10;424(6945):213-9.
transparent image
30.   Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278:1295-300.
transparent image
31.   Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, Hermankova M, Chadwick K, Margolick J, Quinn TC, Kuo YH, Brookmeyer R, Zeiger MA, Barditch-Crovo P, Siliciano RF. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387:183-8.
transparent image
32.   Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA, Reinhart TA, Rogan M, Cavert W, Miller CJ, Veazey RS, Notermans D, Little S, Danner SA, Richman DD, Havlir D, Wong J, Jordan HL, Schacker TW, Racz P, Tenner-Racz K, Letvin NL, Wolinsky S, Haase AT. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 1999; 286:1353-7.
transparent image
33.   Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997 Nov 14;278(5341):1295-300.
transparent image
34.   Zhang H, Dornadula G, Beumont M, Livornese L, Jr., Van Uitert B, Henning K, Pomerantz RJ. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med 1998; 339:1803-9.
transparent image
35.   Bagasra O, Farzadegan H, Seshamma T, Oakes JW, Saah A, Pomerantz RJ. Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. Aids 1994; 8:1669-74.
transparent image
36.   Harrold SM, Wang G, McMahon DK, Riddler SA, Mellors JW, Becker JT, Caldararo R, Reinhart TA, Achim CL, Wiley CA. Recovery of replication-competent HIV type 1-infected circulating monocytes from individuals receiving antiretroviral therapy. AIDS Res Hum Retroviruses 2002; 18:427-34.
transparent image
37.   Sonza S, Mutimer HP, Oelrichs R, Jardine D, Harvey K, Dunne A, Purcell DF, Birch C, Crowe SM. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. Aids 2001; 15:17-22.
transparent image
38.   Zhu T, Muthui D, Holte S, Nickle D, Feng F, Brodie S, Hwangbo Y, Mullins JI, Corey L. Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. J Virol 2002; 76:707-16.
transparent image
39.   Brack-Werner R. Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. Aids 1999; 13:1-22.
transparent image
40.   Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D'Agati VD, Klotman PE, Klotman ME. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med 2001; 344:1979-84.
transparent image
41.   Strain MC, Gunthard HF, Havlir DV, Ignacio CC, Smith DM, Leigh-Brown AJ, Macaranas TR, Lam RY, Daly OA, Fischer M, Opravil M, Levine H, Bacheler L, Spina CA, Richman DD, Wong JK. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci U S A 2003; 100:4819-24.
transparent image
42.   Kulkosky J, Nunnari G, Otero M, Calarota S, Dornadula G, Zhang H, Malin A, Sullivan J, Xu Y, DeSimone J, Babinchak T, Stern J, Cavert W, Haase A, Pomerantz RJ. Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy. J Infect Dis 2002; 186:1403-11.
transparent image
43.   Stellbrink HJ, van Lunzen J, Westby M, O'Sullivan E, Schneider C, Adam A, Weitner L, Kuhlmann B, Hoffmann C, Fenske S, Aries PS, Degen O, Eggers C, Petersen H, Haag F, Horst HA, Dalhoff K, Mocklinghoff C, Cammack N, Tenner-Racz K, Racz P. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). Aids 2002; 16:1479-87.
transparent image
44.   Fraser C, Ferguson NM, Ghani AC, Prins JM, Lange JM, Goudsmit J, Anderson RM, de Wolf F. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. Aids 2000; 14:659-69.
transparent image
45.   Pomerantz RJ. HIV-1 reservoirs. Clin Lab Med 2002; 22:651-80, vi.
transparent image
46.   Pomerantz RJ. Reservoirs, sanctuaries, and residual disease: the hiding spots of HIV-1. HIV Clin Trials 2003; 4:137-43.
transparent image
47.   Pomerantz RJ. HIV: cross-talk and viral reservoirs. Nature 2003; 424:136-7.
transparent image
48.   Sonza S, Crowe SM. Reservoirs for HIV infection and their persistence in the face of undetectable viral load. AIDS Patient Care STDS 2001; 15:511-8.
transparent image
49.   Masur H, Ognibene FP, Yarchoan R, Shelhamer JH, Baird BF, Travis W, Suffredini AF, Deyton L, Kovacs JA, Falloon J, et al. CD4 counts as predictors of opportunistic pneumonias in human immunodeficiency virus (HIV) infection. Ann Intern Med 1989; 111:223-31.
transparent image
50.   Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest 1995; 95:2061-6.
transparent image
51.   Clerici M, Stocks NI, Zajac RA, Boswell RN, Lucey DR, Via CS, Shearer GM. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest 1989; 84:1892-9.
transparent image
52.   Sieg SF, Bazdar DA, Harding CV, Lederman MM. Differential expression of interleukin-2 and gamma interferon in human immunodeficiency virus disease. J Virol 2001; 75:9983-5.
transparent image
53.   Sieg SF, Harding CV, Lederman MM. HIV-1 infection impairs cell cycle progression of CD4(+) T cells without affecting early activation responses. J Clin Invest 2001; 108:757-64.
transparent image
54.   Sieg SF, Mitchem JB, Bazdar DA, Lederman MM. Close link between CD4+ and CD8+ T cell proliferation defects in patients with human immunodeficiency virus disease and relationship to extended periods of CD4+ lymphopenia. J Infect Dis 2002; 185:1401-16.
transparent image
55.   Margolick JB, Munoz A, Donnenberg AD, Park LP, Galai N, Giorgi JV, O'Gorman MR, Ferbas J. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort Study. Nat Med 1995; 1:674-80.
transparent image
56.   Rook AH, Manischewitz JF, Frederick WR, Epstein JS, Jackson L, Gelmann E, Steis R, Masur H, Quinnan GV, Jr. Deficient, HLA-restricted, cytomegalovirus-specific cytotoxic T cells and natural killer cells in patients with the acquired immunodeficiency syndrome. J Infect Dis 1985; 152:627-30.
transparent image
57.   Zhang D, Shankar P, Xu Z, Harnisch B, Chen G, Lange C, Lee SJ, Valdez H, Lederman MM, Lieberman J. Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 2003; 101:226-235.
transparent image
58.   Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, Van Baarle D, Kostense S, Miedema F, McLaughlin M, Ehler L, Metcalf J, Liu S, Connors M. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3:1061-8.
transparent image
59.   Shirai A, Cosentino M, Leitman-Klinman SF, Klinman DM. Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J Clin Invest 1992; 89:561-6.
transparent image
60.   Nagase H, Agematsu K, Kitano K, Takamoto M, Okubo Y, Komiyama A, Sugane K. Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin Immunol 2001; 100:250-9.
transparent image
61.   Martinez-Maza O, Crabb E, Mitsuyasu RT, Fahey JL, Giorgi JV. Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity. J Immunol 1987; 138:3720-4.
transparent image
62.   Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, Ehler LA, Liu S, Adelsberger J, Lapointe R, Hwu P, Baseler M, Orenstein JM, Chun TW, Mican JA, Fauci AS. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A 2001; 98:10362-7.
transparent image
63.   Chretien P, Monier JC, Oksman F, San Marco M, Escande A, Goetz J, Cohen J, Baquey A, Humbel RL, Sibilia J. Autoantibodies and human immunodeficiency viruses infection: a case-control study. Clin Exp Rheumatol 2003; 21:210-2.
transparent image
64.   Martinez-Maza O, Breen EC. B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol 2002; 14:528-32.
transparent image
65.   Stohl W, Cheema GS, Briggs WS, Xu D, Sosnovtseva S, Roschke V, Ferrara DE, Labat K, Sattler FR, Pierangeli SS, Hilbert DM. B lymphocyte stimulator protein-associated increase in circulating autoantibody levels may require CD4+ T cells: lessons from HIV-infected patients. Clin Immunol 2002; 104:115-22.
transparent image
66.   Rodriguez B, Valdez H, Freimuth W, Butler T, Asaad R, Lederman MM. Plasma levels of B-lymphocyte stimulator increase with HIV disease progression. Aids 2003; 17:1983-5.
transparent image
67.   Conge AM, Tarte K, Reynes J, Segondy M, Gerfaux J, Zembala M, Vendrell JP. Impairment of B-lymphocyte differentiation induced by dual triggering of the B-cell antigen receptor and CD40 in advanced HIV-1-disease. Aids 1998; 12:1437-49.
transparent image
68.   Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983; 309:453-8.
transparent image
69.   Pahwa SG, Quilop MT, Lange M, Pahwa RN, Grieco MH. Defective B-lymphocyte function in homosexual men in relation to the acquired immunodeficiency syndrome. Ann Intern Med 1984; 101:757-63.
transparent image
70.   Steinhoff MC, Auerbach BS, Nelson KE, Vlahov D, Becker RL, Graham NM, Schwartz DH, Lucas AH, Chaisson RE. Antibody responses to Haemophilus influenzae type B vaccines in men with human immunodeficiency virus infection. N Engl J Med 1991; 325:1837-42.
transparent image
71.   Valdez H, Smith KY, Landay A, Connick E, Kuritzkes DR, Kessler H, Fox L, Spritzler J, Roe J, Lederman MB, Lederman HM, Evans TG, Heath-Chiozzi M, Lederman MM. Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group. Aids 2000; 14:11-21.
transparent image
72.   Ballet JJ, Sulcebe G, Couderc LJ, Danon F, Rabian C, Lathrop M, Clauvel JP, Seligmann M. Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalized lymphadenopathy. Clin Exp Immunol 1987; 68:479-87.
transparent image
73.   Bernstein LJ, Ochs HD, Wedgwood RJ, Rubinstein A. Defective humoral immunity in pediatric acquired immune deficiency syndrome. J Pediatr 1985; 107:352-7.
transparent image
74.   Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 1986; 233:1089-93.
transparent image
75.   Orenstein JM, Fox C, Wahl SM. Macrophages as a source of HIV during opportunistic infections. Science 1997; 276:1857-61.
transparent image
76.   Beschorner R. Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 2003; 13:231; author reply 231-2.
transparent image
77.   Eilbott DJ, Peress N, Burger H, LaNeve D, Orenstein J, Gendelman HE, Seidman R, Weiser B. Human immunodeficiency virus type 1 in spinal cords of acquired immunodeficiency syndrome patients with myelopathy: expression and replication in macrophages. Proc Natl Acad Sci U S A 1989; 86:3337-41.
transparent image
78.   Blauvelt A, Clerici M, Lucey DR, Steinberg SM, Yarchoan R, Walker R, Shearer GM, Katz SI. Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. J Immunol 1995; 154:3506-15.
transparent image
79.   Twigg HL, 3rd, Weissler JC, Yoffe B, Ball EJ, Lipscomb MF. Monocyte accessory cell function in patients infected with the human immunodeficiency virus. Clin Immunol Immunopathol 1991; 59:436-48.
transparent image
80.   Biggs BA, Hewish M, Kent S, Hayes K, Crowe SM. HIV-1 infection of human macrophages impairs phagocytosis and killing of Toxoplasma gondii. J Immunol 1995; 154:6132-9.
transparent image
81.   Baldwin GC, Fleischmann J, Chung Y, Koyanagi Y, Chen IS, Golde DW. Human immunodeficiency virus causes mononuclear phagocyte dysfunction. Proc Natl Acad Sci U S A 1990; 87:3933-7.
transparent image
82.   Ennen J, Seipp I, Norley SG, Kurth R. Decreased accessory cell function of macrophages after infection with human immunodeficiency virus type 1 in vitro. Eur J Immunol 1990; 20:2451-6.
transparent image
83.   Grassi F, Hosmalin A, McIlroy D, Calvez V, Debre P, Autran B. Depletion in blood CD11c-positive dendritic cells from HIV-infected patients. Aids 1999; 13:759-66.
transparent image
84.   Macatonia SE, Lau R, Patterson S, Pinching AJ, Knight SC. Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology 1990; 71:38-45.
transparent image
85.   Pacanowski J, Kahi S, Baillet M, Lebon P, Deveau C, Goujard C, Meyer L, Oksenhendler E, Sinet M, Hosmalin A. Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection. Blood 2001; 98:3016-21.
transparent image
86.   Donaghy H, Pozniak A, Gazzard B, Qazi N, Gilmour J, Gotch F, Patterson S. Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood 2001; 98:2574-6.
transparent image
87.   Crespo L, Sanclimens G, Montaner B, Perez-Tomas R, Royo M, Pons M, Albericio F, Giralt E. Peptide dendrimers based on polyproline helices. J Am Chem Soc 2002; 124:8876-83.
transparent image
88.   Siegal FP, Lopez C, Fitzgerald PA, Shah K, Baron P, Leiderman IZ, Imperato D, Landesman S. Opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity. J Clin Invest 1986; 78:115-23.
transparent image
89.   Soumelis V, Scott I, Gheyas F, Bouhour D, Cozon G, Cotte L, Huang L, Levy JA, Liu YJ. Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. Blood 2001; 98:906-12.
transparent image
90.   Rook AH, Masur H, Lane HC, Frederick W, Kasahara T, Macher AM, Djeu JY, Manischewitz JF, Jackson L, Fauci AS, Quinnan GV, Jr. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. J Clin Invest 1983; 72:398-403.
transparent image
91.   Lederman MM, Ratnoff OD, Scillian JJ, Jones PK, Schacter B. Impaired cell-mediated immunity in patients with classic hemophilia. N Engl J Med 1983; 308:79-83.
transparent image
92.   Katzman M, Lederman MM. Defective postbinding lysis underlies the impaired natural killer activity in factor VIII-treated, human T lymphotropic virus type III seropositive hemophiliacs. J Clin Invest 1986; 77:1057-62.
transparent image
93.   Lederman MM, Ratnoff OD, Schacter B, Shoger T. Impaired cell-mediated immunity in hemophilia. II. Persistence of subclinical immunodeficiency and enhancement of natural killer activity by lymphokines. J Lab Clin Med 1985; 106:197-204.
transparent image
94.   Martini F, Urso R, Gioia C, De Felici A, Narciso P, Amendola A, Paglia MG, Colizzi V, Poccia F. gammadelta T-cell anergy in human immunodeficiency virus-infected persons with opportunistic infections and recovery after highly active antiretroviral therapy. Immunology 2000; 100:481-6.
transparent image
95.   Wallace M, Scharko AM, Pauza CD, Fisch P, Imaoka K, Kawabata S, Fujihashi K, Kiyono H, Tanaka Y, Bloom BR, Malkovsky M. Functional gamma delta T-lymphocyte defect associated with human immunodeficiency virus infections. Mol Med 1997; 3:60-71.
transparent image
96.   Chervenak KA, Lederman MM, Boom WH. Bacterial antigen activation of Vdelta1 and Vdelta2 gammadelta T cells of persons infected with human immunodeficiency virus type 1. J Infect Dis 1997; 175:429-33.
transparent image
97.   Prince HE, Jensen ER. Three-color cytofluorometric analysis of CD8 cell subsets in HIV-1 infection. J Acquir Immune Defic Syndr 1991; 4:1227-32.
transparent image
98.   Giorgi JV, Detels R. T-cell subset alterations in HIV-infected homosexual men: NIAID Multicenter AIDS cohort study. Clin Immunol Immunopathol 1989; 52:10-8.
transparent image
99.   Hazenberg MD, Stuart JW, Otto SA, Borleffs JC, Boucher CA, de Boer RJ, Miedema F, Hamann D. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood 2000; 95:249-55.
transparent image
100.   Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE. CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 2002; 8:319-23.
transparent image
101.   Sousa AE, Carneiro J, Meier-Schellersheim M, Grossman Z, Victorino RM. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol 2002; 169:3400-6.
transparent image
102.   Giorgi JV, Liu Z, Hultin LE, Cumberland WG, Hennessey K, Detels R. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr 1993; 6:904-12.
transparent image
103.   Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St Clair M, Kotzin BL, Fox L, Chiozzi MH, Leonard JM, Rousseau F, Wade M, Roe JD, Martinez A, Kessler H. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998; 178:70-9.
transparent image
104.   Liu Z, Cumberland WG, Hultin LE, Kaplan AH, Detels R, Giorgi JV. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18:332-40.
transparent image
105.   Bouscarat F, Levacher-Clergeot M, Dazza MC, Strauss KW, Girard PM, Ruggeri C, Sinet M. Correlation of CD8 lymphocyte activation with cellular viremia and plasma HIV RNA levels in asymptomatic patients infected by human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 1996; 12:17-24.
transparent image
106.   Giorgi JV, Lyles RH, Matud JL, Yamashita TE, Mellors JW, Hultin LE, Jamieson BD, Margolick JB, Rinaldo CR, Jr., Phair JP, Detels R. Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J Acquir Immune Defic Syndr 2002; 29:346-55.
transparent image
107.   Betts MR, Casazza JP, Koup RA. Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production. Immunol Lett 2001; 79:117-25.
transparent image
108.   Sachsenberg N, Perelson AS, Yerly S, Schockmel GA, Leduc D, Hirschel B, Perrin L. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J Exp Med 1998; 187:1295-303.
transparent image
109.   Patki AH, Zielske SP, Sieg SF, Lederman MM. Preferential S phase entry and apoptosis of CD4(+) T lymphocytes of HIV-1-infected patients after in vitro cultivation. Clin Immunol 2000; 97:241-7.
transparent image
110.   Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, Schmidt D, Hoh R, Neese R, Macallan D, Deeks S, McCune JM. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999; 5:83-9.
transparent image
111.   Dezube BJ, Lederman MM, Chapman B, Georges DL, Dogon AL, Mudido P, Reis-Lishing J, Cheng SL, Silberman SL, Crumpacker CS. The effect of tenidap on cytokines, acute-phase proteins, and virus load in human immunodeficiency virus (HIV)-infected patients: correlation between plasma HIV-1 RNA and proinflammatory cytokine levels. J Infect Dis 1997; 176:807-10.
transparent image
112.   Andersson J, Fehniger TE, Patterson BK, Pottage J, Agnoli M, Jones P, Behbahani H, Landay A. Early reduction of immune activation in lymphoid tissue following highly active HIV therapy. AIDS. 1998 Jul 30;12(11):F123-9.
transparent image
113.   Brazille P, Dereuddre-Bosquet N, Leport C, Clayette P, Boyer O, Vilde JL, Dormont D, Benveniste O. Decreases in plasma TNF-alpha level and IFN-gamma mRNA level in peripheral blood mononuclear cells (PBMC) and an increase in IL-2 mRNA level in PBMC are associated with effective highly active antiretroviral therapy in HIV-infected patients. Clin Exp Immunol 2003; 131:304-11.
transparent image
114.   Evans TG, Bonnez W, Soucier HR, Fitzgerald T, Gibbons DC, Reichman RC. Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells. Antiviral Res 1998; 39:163-73.
transparent image
115.   Tilling R, Kinloch S, Goh LE, Cooper D, Perrin L, Lampe F, Zaunders J, Hoen B, Tsoukas C, Andersson J, Janossy G. Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection. Aids 2002; 16:589-96.
transparent image
116.   Bisset LR, Cone RW, Huber W, Battegay M, Vernazza PL, Weber R, Grob PJ, Opravil M. Highly active antiretroviral therapy during early HIV infection reverses T-cell activation and maturation abnormalities. Swiss HIV Cohort Study. Aids 1998; 12:2115-23.
transparent image
117.   Burgisser P, Hammann C, Kaufmann D, Battegay M, Rutschmann OT. Expression of CD28 and CD38 by CD8+ T lymphocytes in HIV-1 infection correlates with markers of disease severity and changes towards normalization under treatment. The Swiss HIV Cohort Study. Clin Exp Immunol 1999; 115:458-63.
transparent image
118.   Savarino A, Bensi T, Chiocchetti A, Bottarel F, Mesturini R, Ferrero E, Calosso L, Deaglio S, Ortolan E, Butto S, Cafaro A, Katada T, Ensoli B, Malavasi F, Dianzani U. Human CD38 interferes with HIV-1 fusion through a sequence homologous to the V3 loop of the viral envelope glycoprotein gp120. Faseb J 2003; 17:461-3.
transparent image
119.   Rey-Cuille MA, Berthier JL, Bomsel-Demontoy MC, Chaduc Y, Montagnier L, Hovanessian AG, Chakrabarti LA. Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease. J Virol 1998; 72:3872-86.
transparent image
120.   Chakrabarti LA, Lewin SR, Zhang L, Gettie A, Luckay A, Martin LN, Skulsky E, Ho DD, Cheng-Mayer C, Marx PA. Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection. J Virol 2000; 74:1209-23.
transparent image
121.   Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, McClure HM, Staprans SI, Feinberg MB. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 2003; 18:441-52.
transparent image
122.   Rizzardi GP, Harari A, Capiluppi B, Tambussi G, Ellefsen K, Ciuffreda D, Champagne P, Bart PA, Chave JP, Lazzarin A, Pantaleo G. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest 2002; 109:681-8.
transparent image
123.   Watkins BA, Buge S, Aldrich K, Davis AE, Robinson J, Reitz MS, Jr., Robert-Guroff M. Resistance of human immunodeficiency virus type 1 to neutralization by natural antisera occurs through single amino acid substitutions that cause changes in antibody binding at multiple sites. J Virol 1996; 70:8431-7.
transparent image
124.   Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995; 270:1811-5.
transparent image
125.   Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986; 234:1563-6.
transparent image
126.   Mackewicz CE, Blackbourn DJ, Levy JA. CD8+ T cells suppress human immunodeficiency virus replication by inhibiting viral transcription. Proc Natl Acad Sci U S A 1995; 92:2308-12.
transparent image
127.   Barker E, Bossart KN, Levy JA. Primary CD8+ cells from HIV-infected individuals can suppress productive infection of macrophages independent of beta-chemokines. Proc Natl Acad Sci U S A 1998; 95:1725-9.
transparent image
128.   Moriuchi H, Moriuchi M, Combadiere C, Murphy PM, Fauci AS. CD8+ T-cell-derived soluble factor(s), but not beta-chemokines RANTES, MIP-1 alpha, and MIP-1 beta, suppress HIV-1 replication in monocyte/macrophages. Proc Natl Acad Sci U S A 1996; 93:15341-5.
transparent image
129.   Chang TL, Francois F, Mosoian A, Klotman ME. CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from alpha-Defensin-1 HIV Inhibition. J Virol 2003; 77:6777-84.
transparent image
130.   Barker E, Mackewicz CE, Reyes-Teran G, Sato A, Stranford SA, Fujimura SH, Christopherson C, Chang SY, Levy JA. Virological and immunological features of long-term human immunodeficiency virus-infected individuals who have remained asymptomatic compared with those who have progressed to acquired immunodeficiency syndrome. Blood 1998; 92:3105-14.
transparent image
131.   Blackbourn DJ, Mackewicz CE, Barker E, Hunt TK, Herndier B, Haase AT, Levy JA. Suppression of HIV replication by lymphoid tissue CD8+ cells correlates with the clinical state of HIV-infected individuals. Proc Natl Acad Sci U S A 1996; 93:13125-30.
transparent image
132.   Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995; 332:201-8.
transparent image
133.   Mackewicz CE, Ortega HW, Levy JA. CD8+ cell anti-HIV activity correlates with the clinical state of the infected individual. J Clin Invest 1991; 87:1462-6.
transparent image
134.   Betts MR, Ambrozak DR, Douek DC, Bonhoeffer S, Brenchley JM, Casazza JP, Koup RA, Picker LJ. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol 2001; 75:11983-91.
transparent image
135.   Chouquet C, Autran B, Gomard E, Bouley JM, Calvez V, Katlama C, Costagliola D, Riviere Y. Correlation between breadth of memory HIV-specific cytotoxic T cells, viral load and disease progression in HIV infection. Aids 2002; 16:2399-407.
transparent image
136.   Migueles SA, Connors M. Frequency and function of HIV-specific CD8(+) T cells. Immunol Lett 2001; 79:141-50.
transparent image
137.   Gea-Banacloche JC, Migueles SA, Martino L, Shupert WL, McNeil AC, Sabbaghian MS, Ehler L, Prussin C, Stevens R, Lambert L, Altman J, Hallahan CW, de Quiros JC, Connors M. Maintenance of large numbers of virus-specific CD8+ T cells in HIV-infected progressors and long-term nonprogressors. J Immunol 2000; 165:1082-92.
transparent image
138.   Shankar P, Russo M, Harnisch B, Patterson M, Skolnik P, Lieberman J. Impaired function of circulating HIV-specific CD8(+) T cells in chronic human immunodeficiency virus infection. Blood 2000; 96:3094-101.
transparent image
139.   Phillips RE, Rowland-Jones S, Nixon DF, Gotch FM, Edwards JP, Ogunlesi AO, Elvin JG, Rothbard JA, Bangham CR, Rizza CR, et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 1991; 354:453-9.
transparent image
140.   Price DA, Goulder PJ, Klenerman P, Sewell AK, Easterbrook PJ, Troop M, Bangham CR, Phillips RE. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A 1997; 94:1890-5.
transparent image
141.   Zhang D, Shankar P, Xu Z, Harnisch B, Chen G, Lange C, Lee SJ, Valdez H, Lederman MM, Lieberman J. Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood. 2003 Jan 1;101(1):226-35.
transparent image
142.   Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A, Ogg GS, Spiegel HM, Conlon C, Spina CA, Havlir DV, Richman DD, Waters A, Easterbrook P, McMichael AJ, Rowland-Jones SL. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 2000; 192:63-75.
transparent image
143.   Trimble LA, Shankar P, Patterson M, Daily JP, Lieberman J. Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3zeta and CD28, key signaling molecules for T-cell activation. J Virol 2000; 74:7320-30.
transparent image
144.   Wahren B, Morfeldt-Mansson L, Biberfeld G, Moberg L, Sonnerborg A, Ljungman P, Werner A, Kurth R, Gallo R, Bolognesi D. Characteristics of the specific cell-mediated immune response in human immunodeficiency virus infection. J Virol 1987; 61:2017-23.
transparent image
145.   Krowka JF, Stites DP, Jain S, Steimer KS, George-Nascimento C, Gyenes A, Barr PJ, Hollander H, Moss AR, Homsy JM, et al. Lymphocyte proliferative responses to human immunodeficiency virus antigens in vitro. J Clin Invest 1989; 83:1198-203.
transparent image
146.   Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, Picker LJ. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 1999; 5:518-25.
transparent image
147.   Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997; 278:1447-50.
transparent image
148.   Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, Robbins GK, D'Aquila RT, Goulder PJ, Walker BD. Immune control of HIV-1 after early treatment of acute infection. Nature 2000; 407:523-6.
transparent image
149.   McNeil AC, Shupert WL, Iyasere CA, Hallahan CW, Mican JA, Davey RT, Jr., Connors M. High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation. Proc Natl Acad Sci U S A 2001; 98:13878-83.
transparent image
150.   Palmer BE, Boritz E, Blyveis N, Wilson CC. Discordance between frequency of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon-producing CD4(+) T cells and HIV-1-specific lymphoproliferation in HIV-1-infected subjects with active viral replication. J Virol 2002; 76:5925-36.
transparent image
151.   Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease [see comments]. Science. 1997 Jul 4;277(5322):112-6.
transparent image
152.   Lange CG, Lederman MM, Madero JS, Medvik K, Asaad R, Pacheko C, Carranza C, Valdez H. Impact of suppression of viral replication by highly active antiretroviral therapy on immune function and phenotype in chronic HIV- 1 infection. J Acquir Immune Defic Syndr 2002; 30:33-40.
transparent image
153.   Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002; 417:95-8.
transparent image
154.   Mathur-Wagh U, Enlow RW, Spigland I, Winchester RJ, Sacks HS, Rorat E, Yancovitz SR, Klein MJ, William DC, Mildvan D. Longitudinal study of persistent generalised lymphadenopathy in homosexual men: relation to acquired immunodeficiency syndrome. Lancet 1984; 1:1033-8.
transparent image
155.   Metroka CE, Cunningham-Rundles S, Pollack MS, Sonnabend JA, Davis JM, Gordon B, Fernandez RD, Mouradian J. Generalized lymphadenopathy in homosexual men. Ann Intern Med 1983; 99:585-91.
transparent image
156.   Nokta MA, Li XD, Nichols J, Pou A, Asmuth D, Pollard RB. Homeostasis of naive and memory T cell subpopulations in peripheral blood and lymphoid tissues in the context of human immunodeficiency virus infection. J Infect Dis. 2001 May 1;183(9):1336-42.
transparent image
157.   Emilie D, Peuchmaur M, Maillot MC, Crevon MC, Brousse N, Delfraissy JF, Dormont J, Galanaud P. Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes. J Clin Invest 1990; 86:148-59.
transparent image
158.   Galanaud P. The in vivo expression of cytokine genes in humans. J Lipid Mediat Cell Signal 1994; 9:37-41.
transparent image
159.   Boyle MJ, Berger MF, Tschuchnigg M, Valentine JE, Kennedy BG, Divjak M, Cooper DA, Turner JJ, Penny R, Sewell WA. Increased expression of interferon-gamma in hyperplastic lymph nodes from HIV-infected patients. Clin Exp Immunol 1993; 92:100-5.
transparent image
160.   Trumpfheller C, Tenner-Racz K, Racz P, Fleischer B, Frosch S. Expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response. Clin Exp Immunol 1998; 112:92-9.
transparent image
161.   Bucy RP, Hockett RD, Derdeyn CA, Saag MS, Squires K, Sillers M, Mitsuyasu RT, Kilby JM. Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest 1999; 103:1391-8.
transparent image
162.   Schacker TW, Nguyen PL, Beilman GJ, Wolinsky S, Larson M, Reilly C, Haase AT. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest 2002; 110:1133-9.
transparent image
163.   Bolton DL, Hahn BI, Park EA, Lehnhoff LL, Hornung F, Lenardo MJ. Death of CD4(+) T-cell lines caused by human immunodeficiency virus type 1 does not depend on caspases or apoptosis. J Virol 2002; 76:5094-107.
transparent image
164.   Lenardo MJ, Angleman SB, Bounkeua V, Dimas J, Duvall MG, Graubard MB, Hornung F, Selkirk MC, Speirs CK, Trageser C, Orenstein JO, Bolton DL. Cytopathic killing of peripheral blood CD4(+) T lymphocytes by human immunodeficiency virus type 1 appears necrotic rather than apoptotic and does not require env. J Virol 2002; 76:5082-93.
transparent image
165.   Wolthers KC, Bea G, Wisman A, Otto SA, de Roda Husman AM, Schaft N, de Wolf F, Goudsmit J, Coutinho RA, van der Zee AG, Meyaard L, Miedema F. T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 1996; 274:1543-7.
transparent image
166.   Hellerstein MK, McCune JM. T cell turnover in HIV-1 disease. Immunity 1997; 7:583-9.
transparent image
167.   Mohri H, Perelson AS, Tung K, Ribeiro RM, Ramratnam B, Markowitz M, Kost R, Hurley A, Weinberger L, Cesar D, Hellerstein MK, Ho DD. Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J Exp Med 2001; 194:1277-87.
transparent image
168.   Lempicki RA, Kovacs JA, Baseler MW, Adelsberger JW, Dewar RL, Natarajan V, Bosche MC, Metcalf JA, Stevens RA, Lambert LA, Alvord WG, Polis MA, Davey RT, Dimitrov DS, Lane HC. Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc Natl Acad Sci U S A 2000; 97:13778-83.
transparent image
169.   Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, Sereti I, Polis MA, Davey RT, Tavel J, Falloon J, Stevens R, Lambert L, Dewar R, Schwartzentruber DJ, Anver MR, Baseler MW, Masur H, Dimitrov DS, Lane HC. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med 2001; 194:1731-41.
transparent image
170.   Meyaard L, Otto SA, Jonker RR, Mijnster MJ, Keet RP, Miedema F. Programmed death of T cells in HIV-1 infection. Science 1992; 257:217-9.
transparent image
171.   Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, Picker LJ. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med. 1999 May;5(5):518-25.
transparent image
172.   Stanley SK, Kessler SW, Justement JS, Schnittman SM, Greenhouse JJ, Brown CC, Musongela L, Musey K, Kapita B, Fauci AS. CD34+ bone marrow cells are infected with HIV in a subset of seropositive individuals. J Immunol 1992; 149:689-97.
transparent image
173.   Marandin A, Katz A, Oksenhendler E, Tulliez M, Picard F, Vainchenker W, Louache F. Loss of primitive hematopoietic progenitors in patients with human immunodeficiency virus infection. Blood 1996; 88:4568-78.
transparent image
174.   Louache F, Henri A, Bettaieb A, Oksenhendler E, Raguin G, Tulliez M, Vainchenker W. Role of human immunodeficiency virus replication in defective in vitro growth of hematopoietic progenitors. Blood 1992; 80:2991-9.
transparent image
175.   Huang SS, Barbour JD, Deeks SG, Huang JS, Grant RM, Ng VL, McCune JM. Reversal of human immunodeficiency virus type 1-associated hematosuppression by effective antiretroviral therapy. Clin Infect Dis 2000; 30:504-10.
transparent image
176.   Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396:690-5.
transparent image
177.   Douek DC, Koup RA. Evidence for thymic function in the elderly. Vaccine 2000; 18:1638-41.
transparent image
178.   McCune JM, Loftus R, Schmidt DK, Carroll P, Webster D, Swor-Yim LB, Francis IR, Gross BH, Grant RM. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J Clin Invest 1998; 101:2301-8.
transparent image
179.   Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, Sevin A, Pu M, Spritzler J, Chernoff M, Namkung A, Fox L, Martinez A, Waterman K, Fiscus SA, Sha B, Johnson D, Slater S, Rousseau F, Lederman MM. Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect Dis 2003; 187:1924-33.
transparent image
180.   Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, He Y, Jin X, Tuttleton S, Vesanen M, Spiegel H, Kost R, van Lunzen J, Stellbrink HJ, Wolinsky S, Borkowsky W, Palumbo P, Kostrikis LG, Ho DD. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J Exp Med 1999; 190:725-32.
transparent image
181.   Smith KY, Valdez H, Landay A, Spritzler J, Kessler HA, Connick E, Kuritzkes D, Gross B, Francis I, McCune JM, Lederman MM. Thymic size and lymphocyte restoration in patients with human immunodeficiency virus infection after 48 weeks of zidovudine, lamivudine, and ritonavir therapy. J Infect Dis 2000; 181:141-7.
transparent image
182.   Berkowitz RD, Alexander S, Bare C, Linquist-Stepps V, Bogan M, Moreno ME, Gibson L, Wieder ED, Kosek J, Stoddart CA, McCune JM. CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo. J Virol 1998; 72:10108-17.
transparent image
183.   Teixeira L, Valdez H, McCune JM, Koup RA, Badley AD, Hellerstein MK, Napolitano LA, Douek DC, Mbisa G, Deeks S, Harris JM, Barbour JD, Gross BH, Francis IR, Halvorsen R, Asaad R, Lederman MM. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. Aids 2001; 15:1749-56.
transparent image
184.   Fabbi M, Groh V, Strominger JL. IL-7 induces proliferation of CD3-/low CD4- CD8- human thymocyte precursors by an IL-2 independent pathway. Int Immunol 1992; 4:1-5.
transparent image
185.   Murray R, Suda T, Wrighton N, Lee F, Zlotnik A. IL-7 is a growth and maintenance factor for mature and immature thymocyte subsets. Int Immunol 1989; 1:526-31.
transparent image
186.   Vissinga CS, Fatur-Saunders DJ, Takei F. Dual role of IL-7 in the growth and differentiation of immature thymocytes. Exp Hematol 1992; 20:998-1003.
transparent image
187.   Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, Herndier BG, Andersson J, McCune JM. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med 2001; 7:73-9.
transparent image
188.   Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, Steinberg SM, Wood LV, Yarchoan R, Zuckerman J, Landay A, Mackall CL. A potential role for interleukin-7 in T-cell homeostasis. Blood 2001; 97:2983-90.
transparent image
189.   Mellors JW, Kingsley LA, Rinaldo CR, Jr., Todd JA, Hoo BS, Kokka RP, Gupta P. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med 1995; 122:573-9.
transparent image
190.   Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J Med 2001; 344:720-5.
transparent image
191.   Learmont J, Tindall B, Evans L, Cunningham A, Cunningham P, Wells J, Penny R, Kaldor J, Cooper DA. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet 1992; 340:863-7.
transparent image
192.   Gurusinghe AD, Land SA, Birch C, McGavin C, Hooker DJ, Tachedjian G, Doherty R, Deacon NJ. Reverse transcriptase mutations in sequential HIV-1 isolates in a patient with AIDS. J Med Virol 1995; 46:238-43.
transparent image
193.   Quinones-Mateu ME, Mas A, Lain de Lera T, Soriano V, Alcami J, Lederman MM, Domingo E. LTR and tat variability of HIV-1 isolates from patients with divergent rates of disease progression. Virus Res 1998; 57:11-20.
transparent image
194.   Zhang L, Huang Y, Yuan H, Chen BK, Ip J, Ho DD. Genotypic and phenotypic characterization of long terminal repeat sequences from long-term survivors of human immunodeficiency virus type 1 infection. J Virol 1997; 71:5608-13.
transparent image
195.   Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use coreceptor use correlates with disease progression in HIV-1--infected individuals. J Exp Med 1997; 185:621-8.
transparent image
196.   Back NK, Nijhuis M, Keulen W, Boucher CA, Oude Essink BO, van Kuilenburg AB, van Gennip AH, Berkhout B. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. Embo J 1996; 15:4040-9.
transparent image
197.   Sharma PL, Crumpacker CS. Attenuated replication of human immunodeficiency virus type 1 with a didanosine-selected reverse transcriptase mutation. J Virol 1997; 71:8846-51.
transparent image
198.   Croteau G, Doyon L, Thibeault D, McKercher G, Pilote L, Lamarre D. Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol 1997; 71:1089-96.
transparent image
199.   Kuroda MJ, el-Farrash MA, Choudhury S, Harada S. Impaired infectivity of HIV-1 after a single point mutation in the POL gene to escape the effect of a protease inhibitor in vitro. Virology 1995; 210:212-6.
transparent image
200.   Deeks SG, Wrin T, Liegler T, Hoh R, Hayden M, Barbour JD, Hellmann NS, Petropoulos CJ, McCune JM, Hellerstein MK, Grant RM. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344:472-80.
transparent image
201.   Deeks SG, Hoh R, Grant RM, Wrin T, Barbour JD, Narvaez A, Cesar D, Abe K, Hanley MB, Hellmann NS, Petropoulos CJ, McCune JM, Hellerstein MK. CD4+ T cell kinetics and activation in human immunodeficiency virus-infected patients who remain viremic despite long-term treatment with protease inhibitor-based therapy. J Infect Dis 2002; 185:315-23.
transparent image
202.   Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K, Kunstman K, Erickson D, Dragon E, Landau NR, Phair J, Ho DD, Koup RA. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med 1996; 2:1240-3.
transparent image
203.   Ioannidis JP, Rosenberg PS, Goedert JJ, Ashton LJ, Benfield TL, Buchbinder SP, Coutinho RA, Eugen-Olsen J, Gallart T, Katzenstein TL, Kostrikis LG, Kuipers H, Louie LG, Mallal SA, Margolick JB, Martinez OP, Meyer L, Michael NL, Operskalski E, Pantaleo G, Rizzardi GP, Schuitemaker H, Sheppard HW, Stewart GJ, Theodorou ID, Ullum H, Vicenzi E, Vlahov D, Wilkinson D, Workman C, Zagury JF, O'Brien TR. Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual- patient data. Ann Intern Med 2001; 135:782-95.
transparent image
204.   Salkowitz JR, Bruse SE, Meyerson H, Valdez H, Mosier DE, Harding CV, Zimmerman PA, Lederman MM. CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro. Clin Immunol 2003; 108:234-40.
transparent image
205.   Liu H, Chao D, Nakayama EE, Taguchi H, Goto M, Xin X, Takamatsu JK, Saito H, Ishikawa Y, Akaza T, Juji T, Takebe Y, Ohishi T, Fukutake K, Maruyama Y, Yashiki S, Sonoda S, Nakamura T, Nagai Y, Iwamoto A, Shioda T. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression. Proc Natl Acad Sci U S A 1999; 96:4581-5.
transparent image
206.   Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, O'Brien TR, Jacobson LP, Detels R, Donfield S, Willoughby A, Gomperts E, Vlahov D, Phair J, O'Brien SJ. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC). Science 1998; 279:389-93.
transparent image
207.   Carrington M, O'Brien SJ. The influence of HLA genotype on AIDS. Annu Rev Med 2003; 54:535-51.
transparent image
208.   Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah AJ, Goedert JJ, Winkler C, O'Brien SJ, Rinaldo C, Detels R, Blattner W, Phair J, Erlich H, Mann DL. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996; 2:405-11.
transparent image
209.  Mallal SA, Moore CB, Carvalho F, Patterson A, Liu C, Goodridge D, Sayer D, James I, John M. HIV adaptation to HLA-restricted immune responses-Implications for vaccine design and evaluation. 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, MA. Abstract 327.
transparent image
210.   Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ, Kaslow R, Buchbinder S, Hoots K, O'Brien SJ. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999; 283:1748-52.
transparent image
211.   Gao X, Nelson GW, Karacki P, Martin MP, Phair J, Kaslow R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, O'Brien SJ, Carrington M. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med 2001; 344:1668-75.
transparent image
212.   Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, Trowsdale J, Wilson M, O'Brien SJ, Carrington M. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31:429-34.
transparent image
213.   Fahey JL, Taylor JM, Detels R, Hofmann B, Melmed R, Nishanian P, Giorgi JV. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med 1990; 322:166-72.
transparent image
214.   Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:83-92.
transparent image
215.   Giorgi JV, Liu Z, Hultin LE, Cumberland WG, Hennessey K, Detels R. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1993 Aug;6(8):904-12.
transparent image
216.   Carbone J, Gil J, Benito JM, Navarro J, Munoz-Fernandez A, Bartolome J, Zabay JM, Lopez F, Fernandez-Cruz E. Increased levels of activated subsets of CD4 T cells add to the prognostic value of low CD4 T cell counts in a cohort of HIV-infected drug users. Aids 2000; 14:2823-9.
transparent image
217.   Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003; 187:1534-43.
transparent image
218.   Lederman MM, Kalish LA, Asmuth D, Fiebig E, Mileno M, Busch MP. 'Modeling' relationships among HIV-1 replication, immune activation and CD4+ T-cell losses using adjusted correlative analyses. Aids 2000; 14:951-8.
transparent image
219.   Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119-29.
transparent image
220.   Lange CG, Lederman MM, Medvik K, Asaad R, Wild M, Kalayjian R, Valdez H. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. Aids 2003; 17:2015-23.
transparent image
221.   Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA; ART Cohort Collaboration. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002 Jul 13;360(9327):119-29.Erratum in: Lancet 2002 Oct 12;360(9340):1178.
transparent image
transparent image