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HHV8
Human Herpesvirus-8, Kaposi Sarcoma, and AIDS-Associated Neoplasms
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Introduction
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Discovery of HHV-8 and Its Disease Associations
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The Epidemiology of HHV-8
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The Virology of HHV-8
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transparent imageHHV-8 Genome
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transparent imageHHV-8 Virion Structure
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transparent imageLatent HHV-8 Infection
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transparent imageInduction of Lytic Replication
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transparent imageHHV-8 Cellular Homologues
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transparent imageHHV-8 Cellular Tropism
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transparent imageHHV-8 Replication
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transparent imageSites of HHV-8 Replication
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transparent imageThe Natural History of HHV-8 Shedding
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transparent imagePredictors of HHV-8 Shedding
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transparent imageThe Frequency and Correlates of HHV-8 Viremia
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transparent imageAntiviral Therapy and HHV-8 Replication
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transparent imageSpecies Specificity of HHV-8
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Perspective
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References
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Tables
Table 1.HHV-8 Subtypes and Their Geographic Predominance
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Related Resources
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transparent imagePatient and Community Education
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Introduction
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In 1981, the emergence of Kaposi sarcoma (KS) among young gay men in New York, Los Angeles, and San Francisco heralded the beginning of the AIDS pandemic.(1,2) Previously recognized as an uncommon malignancy of elderly Mediterranean men, African children, and Ashkenazi Jews, KS became the most common neoplasm of AIDS patients. Nearly 40% of persons infected with HIV in the mid-1980s developed KS,(3) and the condition rapidly became associated with the "face of AIDS," portrayed in popular film, theater, and print media. By the end of that decade, the number of new KS cases began to decline, perhaps due to the introduction of antiretroviral therapy (ART). The widespread use of effective ART in the United States and Western Europe has resulted in a 3-fold decrease in the incidence of KS as compared with the early years of the HIV epidemic.(4,5) However, other AIDS-associated malignancies have declined, leaving KS the most common AIDS-associated malignancy.(6) Furthermore, KS continues to be a common affliction among persons with HIV worldwide. In 1994, Chang and Moore established that a novel human herpesvirus, human herpesvirus-8 (HHV-8), also known as KS-associated herpesvirus, was responsible for the development of KS.(7) This chapter includes a review of the virology and epidemiology of HHV-8 and its relationship to the development of KS and other AIDS-related neoplasms.

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Discovery of HHV-8 and Its Disease Associations
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From the earliest days of the AIDS pandemic, it has been clear that patients with HIV disease are at increased risk for neoplastic events. KS was recognized at the outset of the pandemic as a marker for AIDS and, as management of lethal opportunistic infections improved in the years that followed, other AIDS-related neoplasms--most notably B-cell lymphomas--were identified. Although defects in immune surveillance might be expected to contribute powerfully to the risk of neoplastic disease, it has long been speculated that some of this increased cancer risk might be due to the enhanced acquisition of exogenous oncogenic pathogens. Early work centered on defining the roles of Epstein-Barr virus (EBV) and human papillomavirus in AIDS-related lymphomas and anogenital neoplasms (see Anogenital Neoplasia and HIV), respectively. Perhaps the most striking advances in this area, however, have come with the identification and propagation of HHV-8.

Early notions of AIDS-KS biogenesis linked KS development primarily to HIV infection. AIDS patients are excessively at risk for developing KS (20,000 times that of the general population, and 70 times that of other immunosuppressed populations),(3) a fact that early on suggested HIV might make a specific and critical contribution to KS etiology. The HIV genome was not found within KS tumor cells, however, so any involvement of HIV in KS tumorigenesis would have to be indirect. Strong evidence for such indirect involvement was advanced by studies showing that HIV-infected cells can produce extracellular factors that potentiate the growth of KS tumor cells in vitro.(8-11,12,13) Factors released from these cells, in turn, can promote angiogenesis in vivo.(14-16) This finding led to the formulation of a model for AIDS-KS pathogenesis in which the inciting event--cell proliferation--is triggered by growth factors released from HIV-infected cells.(8)

The search for a new virus in KS tumors was motivated principally by powerful epidemiologic studies that pointed to the involvement of a sexually transmitted factor other than HIV in KS tumorigenesis.(17) Among AIDS patients, KS disproportionately affected men who have sex with men (MSM). In the United States, <3% of people who acquired HIV by nonsexual routes (eg, hemophiliacs and other transfusion recipients) developed KS, and KS is even less prevalent among children who acquire HIV by vertical transmission. Furthermore, the risk of developing KS was strongly related to the presence of other sexually transmitted diseases, various sexual behaviors, and the number of sex partners.(2,3,18-20,21) These observations indicated that, within AIDS cohorts, KS risk did not track with HIV itself but with some other agent, practice, or factor that appeared to be linked to sexual behavior. These data challenged the view that HIV is the sole determinant of KS etiology and triggered a search for exogenous pathogens in KS tumors.

A major breakthrough occurred in 1994 when Chang, Moore, and their collaborators,(7) using a technique based on the polymerase chain reaction (PCR), identified 2 small fragments of DNA that were reproducibly present in AIDS-KS specimens but absent in most non-KS tissues. The nucleotide sequences of these 2 fragments revealed homology to 2 known gamma- (lymphotropic) herpesviruses, indicating that these fragments were derived from a novel herpes viral genome. These sequences are found in virtually all AIDS-KS tumors,(22) and are not found in most normal tissues derived from patients at low risk for KS. Subsequent work in many laboratories has shown that the sequences are also regularly found in KS specimens from HIV-negative individuals,(23-27) indicating that this genome is more tightly linked to KS than is that of HIV. The finding also suggests that the association of this virus with KS is not the trivial result of HHV-8 reactivation in profoundly immunodeficient hosts, because HIV-negative KS patients are not significantly immunosuppressed.

Once the association between HHV-8 and KS was established, other AIDS-related neoplasms were examined for the presence of viral DNA. To date, this effort has shown that most AIDS-related B-cell lymphomas are not associated with HHV-8.(28) One rare subtype of lymphoma is linked to HHV-8, however: the so-called body cavity-based lymphoma, or primary effusion lymphoma (PEL).(28) These tumors present as malignant effusions of pleural or peritoneal cavities in the absence of bulky lymphadenopathy, and many also harbor EBV DNA. In addition, HHV-8 DNA is found in lymph nodes from AIDS patients with multicentric Castleman disease (MCD),(29) a complex lymphoproliferative disorder characterized by fever, adenopathy, splenomegaly, and elevated levels of human interleukin-6 (IL-6) in the circulation.(30) Non-HIV-associated forms of MCD also exist, and HHV-8 DNA is present in a subset of such cases. Interestingly, an association between MCD and KS had been previously recognized clinically.(30) Associations between other diseases and HHV-8 have been suggested based on the finding of HHV-8 DNA by PCR in clinical specimens obtained from affected patients. These diseases include multiple myeloma (31-34) sarcoidosis,(35) and multiple sclerosis.(36) Subsequent studies failed to find reliable associations between these diseases and HHV-8 infection, highlighting the importance of using consistent PCR primer sets and stringent controls in seeking HHV-8 disease associations.(37) Shortly after the discovery of HHV-8, serologic assays were developed to more efficiently characterize the prevalence of HHV-8 in various populations, examine associations with other diseases, and determine predictors of infection among high-risk groups (see below). Studies using these assays confirmed the association between HHV-8 infection and KS, PEL, and MCD. Similarly, no association between HHV-8 and a number of common neoplasms was detected in a large, population-based serologic survey in South Africa.(38)

The spectrum of HHV-8-related diseases may not have been completely described to date. HHV-8 recently has been associated with primary pulmonary hypertension in 2 small studies,(39,40) while a "primary HHV-8 infection syndrome" was described in immunocompetent children.(41) Improvements in molecular biologic techniques and increased understanding about the pathogenesis of HHV-8 infection may result in the description of additional human illnesses associated with HHV-8 infection.

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The Epidemiology of HHV-8
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Serologic assays capable of identifying persons infected with HHV-8 have made epidemiologic studies of HHV-8 feasible. As HHV-8 cannot be cultivated readily, the diagnosis of infection with HHV-8 relies either on assessing the antibody response to infection or on detecting viral nucleic acid in clinical specimens. The antibody response to HHV-8 is incompletely understood. HHV-8 expresses proteins differentially, depending on whether it is in a latent or lytic stage of infection,(42) and serologic testing therefore must be able to detect antibodies to both latent and lytic antigens. The initial serologic assays for HHV-8 utilized a cell line isolated from a patient with PEL.(28,43,44) These cells express HHV-8 latent antigens until exogenously stimulated, at which time lytic antigens are produced. An immunofluorescence assay (IFA) that could quantitatively measure serum antibodies to latent and lytic HHV-8 was developed. It was observed that HHV-8 antibody titers in persons with KS were more than 4-fold higher than titers observed in persons without KS but with significant risk for HHV-8 infection.(45) Evaluating the accuracy and reliability of HHV-8 serodiagnostic testing has been challenging for 3 reasons. First, the finding of increased antibody titers in persons with KS makes problematic the use of those persons as a "gold standard" for HHV-8 infection, as an ideal assay would also be able to detect persons asymptomatically infected with HHV-8. Additionally, the inability to find a population that is unequivocally not infected with HHV-8 is a challenge, as risk factors for infection are not completely characterized and the virus may be transmitted through saliva in otherwise low-risk populations. Finally, a longitudinal study of 5 persons identified with primary HHV-8 infection showed that 4 of the 5 persons lost IFA-detectable antibodies to lytic antigens within 5 years following infection despite persistent HHV-8 viremia.(46) With these limitations in mind, the sensitivity and specificity of various assays have been investigated. The use of the latent and lytic IFA in combination was found to be approximately 90% sensitive for detecting HHV-8 infection among persons with KS, but the assay correlated poorly with other assays among HIV-positive patients without KS and it was only approximately 75% specific for HHV-8 infection.(47,48) Enzyme immunoassays (EIAs) have subsequently been developed, with differing antigenic targets, including latent and lytic proteins as well as whole viral lysate.(49) These assays offer the advantages of improved specificity and simplified protocols, but have not been found to be as sensitive as IFAs.(47) Western blots also have been evaluated, with most studies finding that test characteristics are not significantly different from IFAs or EIAs, but the labor-intensive nature of the assay makes immunoblotting less practical.(45,50-52) Multiple testing algorithms have been suggested as the optimal method for the serologic detection of HHV-8 infection.(47,53)

Using various serologic assays, many studies have found that the prevalence of HHV-8 infection varies widely, from approximately 1-3% of blood donors in North America to more than 70% in regions of Africa where HHV-8 is endemic. The prevalence of HHV-8 infection approximately mirrors the prevalence of KS. A relatively high seroprevalence of HHV-8 has been described among injection drug users and women with multiple sexual partners,(54,55) although the incidence of KS among these groups is negligible. HHV-8 seroprevalence also has been shown to be higher among family members of HHV-8-seropositive persons.(56,57) In regions where the virus is endemic, the highest degree of concordant seropositivity is found between mother and child or sibling pairs, and seropositivity is unusual before the age of 5.(57) Taken together, these studies suggest that vertical or parenteral transmission of HHV-8 is rare and inefficient. However, the high prevalence of HHV-8 in children in most endemic regions also argues against sexual contact as the predominant mode of transmission.

Despite well-defined pockets of HHV-8 within populations, definitive risk factors for infection have not been identified. Among MSM, a sexual route of acquisition has been suggested.(58) No set of sexual behaviors, however, has been consistently associated with HHV-8 infection in epidemiologic studies. These discrepant data may be explained by a number of factors. First, the populations enrolled in each study may have differed in their practice of sexual behaviors. Next, the risk factors were not ascertained uniformly among all studies, making their comparison problematic. In particular, kissing was not assessed systematically in any but 1 study and other oral contact was inconsistently measured. Correlates of incident infection were assessed in only 2 cohorts,(59,60) with prevalent infection being assessed in the remainder of the studies. Finally, the serologic assays for HHV-8 infection have varied in accuracy, and this may contribute to the difficulty in identifying risk factors for transmission.

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The Virology of HHV-8
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In the decade since the discovery of HHV-8, significant advances have been made in the basic understanding of the virology of HHV-8 infection. The entire HHV-8 genome has been sequenced and the structure of the virion has been established. Research has elucidated the tissue tropism of the virus, the genes and gene products associated with latency and lytic replication have been characterized, and the complicated interplay between the virus and the human immune system is beginning to be described. A synopsis of this research is included below.

Cultivation of HHV-8 has been challenging, and meaningful advances in the understanding of HHV-8 virology were made only after the identification of a cell line in which viral replication could be observed.(61) This line, body cavity-based lymphoma-1 (BCBL-1), is derived from an AIDS-related body cavity lymphoma and contains HHV-8 DNA in a latent state.(62,63) Viral gene expression is strongly restricted under normal growth conditions, but upon treatment with phorbol esters, BCBL-1 cells efficiently switch to lytic replication, yielding substantial quantities of progeny virions.(61) Thus, this process allows the systematic study of both the latent and lytic phases of the viral life cycle. Advances with in situ hybridization, PCR techniques, and gene arrays have also contributed to a more complete understanding of the virology of HHV-8.

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HHV-8 Genome
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The full HHV-8 genome has been cloned,(64,65) and its DNA sequence has been determined.(66) The genome is a linear, double-stranded DNA of about 165 to 170 kilobases in length.(61) It may also exist in a circular episomal form during latency.(67) Of the viruses that infect humans, HHV-8 is most closely related to the gamma-herpesvirus EBV. However, HHV-8 shares a greater degree of homology with viruses of the genus Rhadinovirus, which includes a simian herpesvirus (the genus prototype herpesvirus saimiri, or HVS),(64) rhesus rhadinovirus (RRV),(68) and murine gamma-herpesvirus 68.(69) The genome's open reading frames are characterized by their similarity to the genus prototype, HVS. More than 80 open reading frames have been identified. They are numbered consecutively from the left-hand side of the genome with the genus-conserved regions prefaced with orf and the frames unique to HHV-8 named K1 through K15.(66) Many of the HHV-8-unique reading frames have been "pirated" from the human genome and may play a role in controlling the cell cycle and cell signaling. One region of the HHV-8 genome, K1, is particularly heterogeneous.(70) The variability in this region has been used to define 6 subtypes (see Table 1) and more than 20 clades of HHV-8. Preliminary molecular epidemiologic studies of virus derived from clinical samples reveal that subtypes cluster by geographic region (see Table 1) and that virus repeatedly detected from the same individual does not vary.(70,71) Superinfection with more than 1 strain of HHV-8, however, has also been reported.(72)

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HHV-8 Virion Structure
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The HHV-8 genome is housed in an icosahedral capsid of approximately 1,200 angstroms in diameter,(73) with a typical herpesvirus envelope and tegument. The capsid differs from alpha- and beta-herpesvirus capsids mostly in its external hexon protrusions, but shares a similar floor structure.

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Latent HHV-8 Infection
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As with all herpesviruses, HHV-8 expresses some genes during latency, whereas others are expressed during the lytic phase of replication. The gene expression program of HHV-8 during each phase has been characterized using a range of techniques, including in situ hybridization (ISH) and gene array technology.(74,75)

During latent HHV-8 infection, 3 genes are expressed from the viral episome: orf72 (viral cyclin D), orf73 (latency-associated nuclear antigen, or LANA-1), and K13 (viral Fas-ligand interleukin-1B-converting enzyme inhibitory protein, or vFLIP). LANA-1 appears to function in a manner analogous to EBNA-1, the predominant antigen expressed during EBV latency. LANA-1 allows for propagation of the viral episome in host cells undergoing mitosis by assuring transcription through the attachment of HHV-8 DNA to the H1 histone on host chromatin.(76) Additionally, all 3 genes play a role in tumorigenesis through control of the cell cycle and regulation of apoptosis. LANA-1 represses the transcriptional activity of p53, preventing its ability to trigger apoptosis.(77) Similarly, vFLIP protects cells latently infected with HHV-8 from apoptosis by preventing the activation of the Fas death receptor pathway (78) and thereby blocking the killing of infected cells by cytotoxic T-cell surveillance.(79) Finally, expression of viral cyclin D overrides host cell-cycle growth arrest imposed by cyclin-dependent kinases and pRb.(80)

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Induction of Lytic Replication
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Methylation of the HHV-8 genome likely plays a role in maintaining latency.(81) Although the precise sequence of events leading to the activation of lytic replication has not been described, the gene product of orf50 (Rta) is necessary and sufficient to initiate the lytic phase of the HHV-8 life cycle.(81-83) After lytic replication is initiated, gene products are made in the ordered sequence typical of other human herpesviruses. The first genes expressed regulate subsequent gene expression, and they are followed by genes that regulate DNA replication, genes necessary for virion production, and genes encoding homologues of cellular proteins.(75)

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HHV-8 Cellular Homologues
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The lytically transcribed cellular homologues may be categorized according to function: those that promote tumor growth, those that assist in evading the human immune response, and those that contribute directly to clinical pathogenesis.

In addition to the latently transcribed genes discussed above that play a role in cellular transformation, both the K1 protein and the viral analogue of B-cell leukemia-2 (vBCL-2) are produced during lytic replication. K1, the gene with the greatest degree of heterogeneity among HHV-8 strains, encodes a transmembrane protein that communicates with B-cell signaling pathways leading to nuclear factor kappa B mediated transcription.(84) With approximately 60% homology to human BCL-2,(85) vBCL-2 was shown to protect human renal embryonic cells (in cell line 293) from apoptosis.(86) Finally, the viral G-protein-coupled receptor (vGPCR) encoded by orf74 has a number of downstream effects mediated through protein kinase pathways leading to endothelial cell survival and growth factor/cytokine production.(87,88) These growth factors may play a direct role in KS pathogenesis, as mice transfected with vGPCR develop tumors with a histology similar to that of KS,(89) while cells transfected with vGPCR secrete vascular endothelial growth factor (VEGF),(90) which is found in excess in KS tumor tissue.(91) HHV-8 also directly produces another human cytokine analogue, viral interleukin-6 (vIL-6), during replication. Although only 25% homologous to IL-6 at the amino acid level, vIL-6 has been shown to induce IL-6 expression (92) and can independently induce proliferation of myeloma cells in culture.(93) Evidencing the role of vIL-6 in the pathophysiology of HHV-8-related tumors, patients with MCD have high levels of IL-6 in the plasma,(94) mice injected with IL-6 develop a lymphoproliferative syndrome similar to MCD,(95) and a patient with MCD treated with a monoclonal antibody to IL-6 experienced disease remissions.(96) The 3 viral macrophage inflammatory proteins (vMIP-I, vMIP-II, and vMIP-III) encoded by the K4 and K6 genes are both proinflammatory and angiogenic. vMIP-II also assists HHV-8 in host immune evasion, possibly by restricting the recruitment of Th1 lymphocytes to HHV-8-infected cells.(97) Other mechanisms the virus has evolved to evade the human immune system include the repression of interferon transcription via the viral interferon regulatory factors (vIRFs), the prevention of class 2 major histocompatibility complex (MHC) -mediated T-cell activation by HHV-8 antigens through K1,(98) and the reduction in number of class 1 MHC molecules on the cell surface via endocytosis induced by K3 and K5.(99)

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HHV-8 Cellular Tropism
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The principal target cell of HHV-8 in KS tumors is the spindle cell, an enigmatic cell that expresses cell surface markers of both endothelial cells and macrophages.(100) The majority of KS-associated spindle cells are infected with HHV-8; conversely, few of the infiltrating inflammatory cells appear to be infected. Thus, the viral genome is present in precisely those cells thought to be at the heart of KS pathogenesis. Most of these cells are latently infected and thus are not producing HHV-8. A small subset of them are expressing lytic cycle genes,(101) however, and electron microscopy confirms that these cells indeed are producing viral progeny.(102)

The tissue tropism of HHV-8 in the nonneoplastic tissues of infected subjects is still being characterized. In AIDS-KS patients, HHV-8 DNA can be found in circulating CD19+ B lymphocytes in 40-50% of cases.(22,103,104) Viral transcripts have also been detected in prostatic epithelial cells (101) and salivary epithelial cells,(105) which is interesting in view of the epidemiologic data for sexual transmission of HHV-8. Although some studies indicate frequent HHV-8 DNA presence in semen,(106) most studies find a low (0-15%) prevalence of seminal HHV-8, even in AIDS-KS patients.(107) It is possible that shedding of HHV-8 into the semen is limited or episodic, perhaps reflecting a low frequency of lytic reactivation in prostatic cells. Viral sequences have also been detected by PCR in the saliva of HHV-8-infected patients, but the role of salivary virus in HHV-8 transmission is not yet clear.(108)

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HHV-8 Replication
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The frequency, quantity, and correlates of HHV-8 replication at mucosal sites (shedding) and viremia continue to be investigated, with the goal of elucidating the mode or modes of HHV-8 transmission and acquisition.

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Sites of HHV-8 Replication
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Although HHV-8 DNA has been recovered from a number of anatomic sites, the frequency with which the virus is found varies by study, population, and sampling technique. A review of all published reports of HHV-8 DNA genitourinary shedding found that HHV-8 DNA was detected in 9% of semen samples and 12% of prostate samples, while detection from anal swabs or cervicovaginal secretions was exceedingly uncommon.(109) In 1 study, a dichotomous pattern of oropharyngeal shedding was observed; HHV-8 seropositive persons either did not shed HHV-8 or shed HHV-8 in high quantities on more than 40% of days sampled.(105) Additionally, HHV-8 DNA quantities were higher in the oropharynx by nearly 2 logs when compared with quantities detected in blood, semen, or prostatic secretions. Finally, the potential for oral epithelial cells to serve as replicative sites for HHV-8, as they do for its closest related human herpesvirus--EBV, is supported by the localization of HHV-8 messenger RNA to oral epithelial cells using in situ hybridization,(105) the detection of HHV-8 latent antigens in salivary glands,(110) and the finding of infectious HHV-8 virions in saliva.(111)

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The Natural History of HHV-8 Shedding
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Little information about the virologic events that surround primary infection with HHV-8 is available. One study found that approximately 10% of MSM with incident HHV-8 infection had HHV-8 DNA detected from serum immediately prior to or after seroconversion.(112) In a separate study, all incident HHV-8 cases among HIV-negative MSM had detectable HHV-8 DNA in peripheral blood mononuclear cells (PBMCs).(46) A more recent report of primary HHV-8 infection in 42 Egyptian children demonstrated that HHV-8 was uniformly found in saliva at the time of primary infection, but concurrent viremia occurred in only 2 of 6 incident cases; no other mucosal sites were sampled.(41)

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Predictors of HHV-8 Shedding
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The predictors of HHV-8 oropharyngeal shedding are also beginning to be explored. The aforementioned study of HHV-8 shedding showed that HIV infection did not appear to influence the frequency of HHV-8 shedding, although the amount of HHV-8 detected was higher in saliva from HIV-positive men.(105) Among men and women infected with HIV and HHV-8, however, those with higher CD4 counts are more likely to have HHV-8 detected in the oropharynx.(113,114) HIV-infected individuals not receiving ART and those with evidence of inflammation in the oral cavity also are at increased risk of HHV-8 shedding, as are persons who have recently developed antibodies to HHV-8.(113)

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The Frequency and Correlates of HHV-8 Viremia
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Previous studies have indicated that 0-10% of HHV-8-infected persons without KS and 0-52% of HHV-8-infected persons with KS are viremic at any given time.(103,105,115-117) The presence of HHV-8 DNA in the blood portends the development of KS in several studies,(103,118,119) and the amount of HHV-8 DNA detected in PBMCs, but not plasma, correlates with clinical KS staging.(120) In HIV-infected individuals, the use of ART reduced the frequency of HHV-8 viremia, an effect similar to what is seen with HHV-8 oropharyngeal shedding.(121,122) The only published longitudinal study of HHV-8 viremia to date showed that viremia persisted for up to 6 months,(112) but no assessment of shedding over time from other anatomic sites has been reported.

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Antiviral Therapy and HHV-8 Replication
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Because the virus is difficult to cultivate, efficacy of antiviral medications against HHV-8 replication has been assessed indirectly. The induction of viral replication in BCBL-1 cells triggered by phorbol esters may be inhibited with ganciclovir and cidofovir,(123,124) while foscarnet and acyclovir variably inhibited lytic replication. Acyclovir, foscarnet, and cidofovir also were shown, via monoclonal antibody staining and flow cytometry, to inhibit the production of lytic gene products after stimulation of BCBL-1 cells.(125) Population-based studies of AIDS patients receiving antivirals for the treatment of other human herpesvirus infections also have been used to determine the effect of these drugs on HHV-8 infection. The use of acyclovir failed to prevent the development of KS,(126) while the use of ganciclovir (127,128) and foscarnet (127,129) was associated with a reduction in the development of KS. Reductions in HHV-8 viremia among AIDS patients receiving ganciclovir or foscarnet were found in 2 studies, although the number of viremic subjects was small in both studies.(130,131) Treatment of HHV-8-related disease with antivirals has met with mixed success. Cidofovir therapy of AIDS-related KS resulted in a reduction of HHV-8 viremia and regression of KS in 1 small series,(132) while a larger series saw no effect on either parameter.(133) Three other HHV-8-associated diseases may be associated with a greater number of cells harboring replicating virus. In the hemophagocytic syndrome (134,135) and PEL,(136) antiviral use led to a remission of symptoms and decreases in HHV-8 viral load. Cidofovir resulted in improvement in MCD and HHV-8 viremia when administered in conjunction with chemotherapy and a monoclonal antibody to IL-6;(137) foscarnet was ineffective in a patient with MCD who died of disseminated KS shortly after its administration;(138) and ganciclovir led to the lasting remission of MCD in 3 HIV-infected patients with the disease.(139)

ART also may have a role in the treatment of HHV-8-related disease independent of its immune-restorative properties in persons with HIV. In addition to the previously mentioned effects on HHV-8 shedding and viremia, zidovudine and stavudine both have been shown to be competitive inhibitors of the HHV-8 thymidine kinase,(140,141) and ritonavir demonstrates a strong antitumorigenic effect against KS.(142,143)

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Species Specificity of HHV-8
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Little is known of the transmissibility of HHV-8 to other species; limited attempts to transmit HHV-8 to another animal host have not been successful. A provocative sighting of an indigenous HHV-8-like agent has been made, however, in primates. Although true KS is not found outside humans, a lesion of primates known as retroperitoneal fibromatosis (RF) shares many features with KS: It appears primarily in animals immunosuppressed by retroviral infection and is characterized by the proliferation of primitive mesenchymal cells and the exuberant induction of aberrant, slitlike neovascular spaces.(144) Strikingly, PCR studies of DNA extracted from RF lesions reveal the presence of herpesviral sequences that are very closely related to HHV-8.(145,146)

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Perspective
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The discovery of HHV-8, its rapid characterization, and the development of therapeutic strategies for HHV-8-related diseases over the past 2 decades serve as a testimony to the power of multidisciplinary approaches to molecular medicine. The first decade was characterized by the search for a novel pathogen responsible for KS. This search was prompted by the astute observations of clinicians, focused by the careful work of epidemiologists, and completed by the ingenuity of molecular biologists. The decade following its discovery has seen a proliferation of knowledge about the virology and pathogenesis of HHV-8. This work has led to effective specific therapies, resulted in significant reductions in morbidity and mortality (see Treatment of HIV-Associated Kaposi Sarcoma, and increased fundamental understanding of oncogenic viruses, tumorigenesis, and immunobiology. As we enter the third decade after the emergence of epidemic KS, the disease remains the most common AIDS-associated malignancy worldwide, with devastating sequelae in Africa, Haiti, and other regions of the developing world. Although ART has reduced the incidence of KS among persons fortunate enough to receive it, it has not eliminated the disease. Furthermore, increasing numbers of iatrogenically immunosuppressed persons has resulted in the recognition of transplant-related KS, and cases of classic and endemic KS continue unabated. A substantial number of persons treated with ART or chemotherapy will not have a complete resolution of their HHV-8-related malignancies.(147) Efficacious and tolerable therapies for these persons with persistent KS, MCD, or PEL are lacking. Finally, efforts to prevent the acquisition of HHV-8 infection are hampered by an incomplete understanding of the mode of HHV-8 transmission. All of these areas motivate the continued study of HHV-8 and its associated clinical diseases, and assure new developments for this emerging field in the years ahead.

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References

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1.   Center for Disease Control. Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. MMWR Morb Mortal Wkly Rep 1981; 30:305-8.
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2.   Hymes KB, Cheung T, Greene JB, Prose NS, Marcus A, Ballard H, William DC, Laubenstein LJ. Kaposi's sarcoma in homosexual men-a report of eight cases. Lancet 1981; 2:598-600.
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3.   Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? . Lancet 1990; 335:123-8.
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4.   Dore GJ, Li Y, Grulich AE, Hoy JF, Mallal SA, Mijch AM, French MA, Cooper DA, Kaldor JM. Declining incidence and later occurrence of Kaposi's sarcoma among persons with AIDS in Australia: the Australian AIDS cohort. Aids 1996; 10:1401-6.
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5.   Joffe MM, Hoover DR, Jacobson LP, Kingsley L, Chmiel JS, Visscher BR. Effect of treatment with zidovudine on subsequent incidence of Kaposi's sarcoma. Clin Infect Dis 1997; 25:1125-33.
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6.   Eltom MA, Jemal A, Mbulaiteye SM, Devesa SS, Biggar RJ. Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer Inst 2002; 94:1204-10.
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7.   Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma Science 1994; 266:1865-9.
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8.   Ensoli B, Barillari G, Gallo RC. Pathogenesis of AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am 1991; 5:281-95.
transparent image
9.   Nakamura S, Salahuddin SZ, Biberfeld P, Ensoli B, Markham PD, Wong-Staal F, Gallo RC. Kaposi's sarcoma cells: long-term culture with growth factor from retrovirus-infected CD4+ T cells. Science 1988; 242:426-30.
transparent image
10.   Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, Cafaro A, Chang HK, Brady JN, Gallo RC. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature 1994; 371:674-80.
transparent image
11.   Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 1990; 345:84-6.
transparent image
12.   Chang J, Renne R, Dittmer D, Ganem D. Inflammatory cytokines and the reactivation of Kaposi's sarcoma-associated herpesvirus lytic replication. Virology 2000; 266:17-25.
transparent image
13.   Fiorelli V, Gendelman R, Samaniego F, Markham PD, Ensoli B. Cytokines from activated T cells induce normal endothelial cells to acquire the phenotypic and functional features of AIDS-Kaposi's sarcoma spindle cells. J Clin Invest 1995; 95:1723-34.
transparent image
14.   Salahuddin SZ, Nakamura S, Biberfeld P, Kaplan MH, Markham PD, Larsson L, Gallo RC. Angiogenic properties of Kaposi's sarcoma-derived cells after long-term culture in vitro. Science 1988; 242:430-3.
transparent image
15.   Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, Larsson L, Beaver B, Wong-Staal F, Gallo RC. AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science 1989; 243:223-6.
transparent image
16.   Miles SA, Rezai AR, Salazar-Gonzalez JF, Vander Meyden M, Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Hirano T, Kishimoto T, et al. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A 1990; 87:4068-72.
transparent image
17.  Beral V. Epidemiology of Kaposi's sarcoma. In: Beral V, Jaffe, HW, Weiss Jr, eds. Cancer Surveys, vol. 10: Cancer, HIV and AIDS. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1991;5-22.
transparent image
18.   Armenian HK, Hoover DR, Rubb S, Metz S, Kaslow R, Visscher B, Chmiel J, Kingsley L, Saah A. Composite risk score for Kaposi's sarcoma based on a case-control and longitudinal study in the Multicenter AIDS Cohort Study (MACS) population. Am J Epidemiol 1993; 138:256-65.
transparent image
19.   Beral V, Bull D, Darby S, Weller I, Carne C, Beecham M, Jaffe H. Risk of Kaposi's sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS Lancet 1992; 339:632-5.
transparent image
20.   Elford J, McDonald A, Kaldor J. Kaposi's sarcoma as a sexually transmissible infection: an analysis of Australian AIDS surveillance data. The National HIV Surveillance Committee. Aids 1993; 7:1667-71.
transparent image
21.   Kaldor JM, Tindall B, Williamson P, Elford J, Cooper DA. Factors associated with Kaposi's sarcoma in a cohort of homosexual and bisexual men. J Acquir Immune Defic Syndr 1993; 6:1145-9.
transparent image
22.   Ambroziak JA, Blackbourn DJ, Herndier BG, Glogau RG, Gullett JH, McDonald AR, Lennette ET, Levy JA. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients. Science 1995; 268:582-3.
transparent image
23.   Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med 1995; 332:1181-5.
transparent image
24.   Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med 1995; 1:707-8.
transparent image
25.   Chuck S, Grant RM, Katongole-Mbidde E, Conant M, Ganem D. Frequent presence of a novel herpesvirus genome in lesions of human immunodeficiency virus-negative Kaposi's sarcoma. J Infect Dis 1996; 173:248-51.
transparent image
26.   Huang YQ, Li JJ, Kaplan MH, Poiesz B, Katabira E, Zhang WC, Feiner D, Friedman-Kien AE. Human herpesvirus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet 1995; 345:759-61.
transparent image
27.   Boshoff C, Whitby D, Hatziioannou T, Fisher C, van der Walt J, Hatzakis A, Weiss R, Schulz T. Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet 1995; 345:1043-4.
transparent image
28.   Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS- related body-cavity-based lymphomas N Engl J Med 1995; 332:1186-91.
transparent image
29.   Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, d'Agay MF, Clauvel JP, Raphael M, Degos L, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 1995; 86:1276-80.
transparent image
30.   Peterson BA, Frizzera G. Multicentric Castleman's disease. Semin Oncol 1993; 20:636-47.
transparent image
31.   Beksac M, Ma M, Akyerli C, DerDanielian M, Zhang L, Liu J, Arat M, Konuk N, Koc H, Ozcelik T, Vescio R, Berenson JR. Frequent demonstration of human herpesvirus 8 (HHV-8) in bone marrow biopsy samples from Turkish patients with multiple myeloma (MM). Leukemia 2001; 15:1268-73.
transparent image
32.   Hsu HC, Lee YM, Yang CF, Hsiao KJ, Liu TT, Ho CK, Ho CH, Wang SY, Liu WT. Detection of Kaposi sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma. Cancer 2001; 91:1409-13.
transparent image
33.   Rettig MB, Ma HJ, Vescio RA, Pold M, Schiller G, Belson D, Savage A, Nishikubo C, Wu C, Fraser J, Said JW, Berenson JR. Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients Science 1997; 276:1851-4.
transparent image
34.   Said JW, Rettig MR, Heppner K, Vescio RA, Schiller G, Ma HJ, Belson D, Savage A, Shintaku IP, Koeffler HP, Asou H, Pinkus G, Pinkus J, Schrage M, Green E, Berenson JR. Localization of Kaposi's sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma. Blood 1997; 90:4278-82.
transparent image
35.   Di Alberti L, Piattelli A, Artese L, Favia G, Patel S, Saunders N, Porter SR, Scully CM, Ngui SL, Teo CG. Human herpesvirus 8 variants in sarcoid tissues Lancet 1997; 350:1655-61.
transparent image
36.   Enbom M. Multiple sclerosis and Kaposi's sarcoma--chronic diseases associated with new human herpesviruses? Scand J Infect Dis 2001; 33:648-58.
transparent image
37.   Pan L, Milligan L, Michaeli J, Cesarman E, Knowles DM. Polymerase chain reaction detection of Kaposi's sarcoma-associated herpesvirus-optimized protocols and their application to myeloma. J Mol Diagn 2001; 3:32-8.
transparent image
38.   Sitas F, Carrara H, Beral V, Newton R, Reeves G, Bull D, Jentsch U, Pacella-Norman R, Bourboulia D, Whitby D, Boshoff C, Weiss R. Antibodies against human herpesvirus 8 in black South African patients with cancer N Engl J Med 1999; 340:1863-71.
transparent image
39.   Bull TM, Cool CD, Serls AE, Rai PR, Parr J, Neid JM, Geraci MW, Campbell TB, Voelkel NF, Badesch DB. Primary pulmonary hypertension, Castleman's disease and human herpesvirus-8. Eur Respir J 2003; 22:403-7.
transparent image
40.   Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003; 349:1113-22.
transparent image
41.   Andreoni M, Sarmati L, Nicastri E, El Sawaf G, El Zalabani M, Uccella I, Bugarini R, Parisi SG, Rezza G. Primary human herpesvirus 8 infection in immunocompetent children. Jama 2002; 287:1295-300.
transparent image
42.   Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, Miller G. A viral gene that activates lytic cycle expression of Kaposi's sarcoma- associated herpesvirus. Proc Natl Acad Sci U S A 1998; 95:10866-71.
transparent image
43.   Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma- associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission [published erratum appears in Nat Med 1996 Sep;2(9):1041]. Nat Med 1996; 2:918-24.
transparent image
44.   Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, Ziegler J, Newton R, Rinaldo CR, Saah A, Phair J, Detels R, Chang Y, Moore PS. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma Nat Med 1996; 2:925-8.
transparent image
45.   Zhu L, Wang R, Sweat A, Goldstein E, Horvat R, Chandran B. Comparison of human sera reactivities in immunoblots with recombinant human herpesvirus (HHV)-8 proteins associated with the latent (ORF73) and lytic (ORFs 65, K8.1A, and K8.1B) replicative cycles and in immunofluorescence assays with HHV-8-infected BCBL-1 cells. Virology 1999; 256:381-92.
transparent image
46.   Wang QJ, Jenkins FJ, Jacobson LP, Kingsley LA, Day RD, Zhang ZW, Meng YX, Pellet PE, Kousoulas KG, Baghian A, Rinaldo CR, Jr. Primary human herpesvirus 8 infection generates a broadly specific CD8(+) T-cell response to viral lytic cycle proteins. Blood 2001; 97:2366-73.
transparent image
47.   Martin JN, Amad Z, Cossen C, Lam PK, Kedes DH, Page-Shafer KA, Osmond DH, Forghani B. Use of epidemiologically well-defined subjects and existing immunofluorescence assays to calibrate a new enzyme immunoassay for human herpesvirus 8 antibodies. J Clin Microbiol 2000; 38:696-701.
transparent image
48.   Rabkin CS, Schulz TF, Whitby D, Lennette ET, Magpantay LI, Chatlynne L, Biggar RJ. Interassay correlation of human herpesvirus 8 serologic tests. HHV-8 Interlaboratory Collaborative Group J Infect Dis 1998; 178:304-9.
transparent image
49.   Sarmati L. Serological testing for human herpesvirus 8. Herpes 2001; 8:76-9.
transparent image
50.   Katano H, Iwasaki T, Baba N, Terai M, Mori S, Iwamoto A, Kurata T, Sata T. Identification of Antigenic Proteins Encoded by Human Herpesvirus 8 and Seroprevalence in the General Population and among Patients with and without Kaposi's Sarcoma. J. Virol. 2000; 74:3478-3485.
transparent image
51.   Lang D, Hinderer W, Rothe M, Sonneborn HH, Neipel F, Raab M, Rabenau H, Masquelier B, Fleury H. Comparison of the immunoglobulin-G-specific seroreactivity of different recombinant antigens of the human herpesvirus 8. Virology 1999; 260:47-54.
transparent image
52.   Spira TJ, Lam L, Dollard SC, Meng YX, Pau CP, Black JB, Burns D, Cooper B, Hamid M, Huong J, Kite-Powell K, Pellett PE. Comparison of serologic assays and PCR for diagnosis of human herpesvirus 8 infection. J Clin Microbiol 2000; 38:2174-80.
transparent image
53.   Casper C, Krantz E, Taylor H, Dalessio J, Carrell D, Wald A, Corey L, Ashley R. Assessment of a combined testing strategy for detection of antibodies to human herpesvirus 8 (HHV-8) in persons with Kaposi's sarcoma, persons with asymptomatic HHV-8 infection, and persons at low risk for HHV-8 infection. J Clin Microbiol 2002; 40:3822-5.
transparent image
54.   Cannon MJ, Dollard SC, Smith DK, Klein RS, Schuman P, Rich JD, Vlahov D, Pellett PE. Blood-borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection. N Engl J Med 2001; 344:637-43.
transparent image
55.   Sosa C, Benetucci J, Hanna C, Sieczkowski L, Deluchi G, Canizal AM, Mantina H, Klaskala W, Baum M, Wood C. Human herpesvirus 8 can be transmitted through blood in drug addicts. Medicina 2001; 61:291-4.
transparent image
56.   Angeloni A, Heston L, Uccini S, Sirianni MC, Cottoni F, Masala MV, Cerimele D, Lin SF, Sun R, Rigsby M, Faggioni A, Miller G. High prevalence of antibodies to human herpesvirus 8 in relatives of patients with classic Kaposi's sarcoma from Sardinia. J Infect Dis 1998; 177:1715-8.
transparent image
57.   Plancoulaine S, Abel L, van Beveren M, Tregouet DA, Joubert M, Tortevoye P, de The G, Gessain A. Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population [In Process Citation]. Lancet 2000; 356:1062-5.
transparent image
58.   Schulz TF. Epidemiology of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. Adv Cancer Res 1999; 76:121-60.
transparent image
59.   Casper C, Wald A, Pauk J, Tabet SR, Corey L, Celum CL. Correlates of prevalent and incident Kaposi's sarcoma-associated herpesvirus infection in men who have sex with men. J Infect Dis 2002; 185:990-3.
transparent image
60.   Dukers NH, Renwick N, Prins M, Geskus RB, Schulz TF, Weverling GJ, Coutinho RA, Goudsmit J. Risk factors for human herpesvirus 8 seropositivity and seroconversion in a cohort of homosexual men Am J Epidemiol 2000; 151:213-24.
transparent image
61.   Renne R, Lagunoff M, Zhong W, Ganem D. The size and conformation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 1996; 70:8151-4.
transparent image
62.   Renne R, Zhong W, Herndier B, McGrath M, Abbey N, Kedes D, Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 1996; 2:342-6.
transparent image
63.   Cesarman E, Moore PS, Rao PH, Inghirami G, Knowles DM, Chang Y. In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood 1995; 86:2708-14.
transparent image
64.   Moore PS, Gao SJ, Dominguez G, Cesarman E, Lungu O, Knowles DM, Garber R, Pellett PE, McGeoch DJ, Chang Y. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. J Virol 1996; 70:549-58.
transparent image
65.   Zhong W, Wang H, Herndier B, Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A 1996; 93:6641-6.
transparent image
66.   Russo JJ, Bohenzky RA, Chien MC, Chen J, Yan M, Maddalena D, Parry JP, Peruzzi D, Edelman IS, Chang Y, Moore PS. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A 1996; 93:14862-7.
transparent image
67.   Lagunoff M, Ganem D. The structure and coding organization of the genomic termini of Kaposi's sarcoma-associated herpesvirus. Virology 1997; 236:147-54.
transparent image
68.   Alexander L, Denekamp L, Knapp A, Auerbach MR, Damania B, Desrosiers RC. The primary sequence of rhesus monkey rhadinovirus isolate 26-95: sequence similarities to Kaposi's sarcoma-associated herpesvirus and rhesus monkey rhadinovirus isolate 17577. J Virol 2000; 74:3388-98.
transparent image
69.   Virgin HW 4th, Latreille P, Wamsley P, Hallsworth K, Weck KE, Dal Canto AJ, Speck SH. Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 1997; 71:5894-904.
transparent image
70.   Zong J-C, Ciufo DM, Alcendor DJ, Wan X, Nicholas J, Browning PJ, Rady PL, Tyring SK, Orenstein JM, Rabkin CS, Su I-J, Powell KF, Croxson M, Foreman KE, Nickoloff BJ, Alkan S, Hayward GS. High-Level Variability in the ORF-K1 Membrane Protein Gene at the Left End of the Kaposi's Sarcoma-Associated Herpesvirus Genome Defines Four Major Virus Subtypes and Multiple Variants or Clades in Different Human Populations. J. Virol. 1999; 73:4156-4170.
transparent image
71.   Zong J, Ciufo DM, Viscidi R, Alagiozoglou L, Tyring S, Rady P, Orenstein J, Boto W, Kalumbuja H, Romano N, Melbye M, Kang GH, Boshoff C, Hayward GS. Genotypic analysis at multiple loci across Kaposi's sarcoma herpesvirus (KSHV) DNA molecules: clustering patterns, novel variants and chimerism. J Clin Virol 2002; 23:119-48.
transparent image
72.   Beyari MM, Hodgson TA, Cook RD, Kondowe W, Molyneux EM, Scully CM, Teo CG, Porter SR. Multiple human herpesvirus-8 infection. J Infect Dis 2003; 188:678-89.
transparent image
73.   Trus BL, Heymann JB, Nealon K, Cheng N, Newcomb WW, Brown JC, Kedes DH, Steven AC. Capsid structure of Kaposi's sarcoma-associated herpesvirus, a gammaherpesvirus, compared to those of an alphaherpesvirus, herpes simplex virus type 1, and a betaherpesvirus, cytomegalovirus. J Virol 2001; 75:2879-90.
transparent image
74.   Sarid R, Flore O, Bohenzky RA, Chang Y, Moore PS. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1). J Virol 1998; 72:1005-12.
transparent image
75.   Paulose-Murphy M, Ha NK, Xiang C, Chen Y, Gillim L, Yarchoan R, Meltzer P, Bittner M, Trent J, Zeichner S. Transcription program of human herpesvirus 8 (kaposi's sarcoma- associated herpesvirus). J Virol 2001; 75:4843-53.
transparent image
76.   Ballestas ME, Chatis PA, Kaye KM. Efficient persistence of extrachromosomal KSHV DNA mediated by latency- associated nuclear antigen. Science 1999; 284:641-4.
transparent image
77.   Friborg J, Jr., Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 1999; 402:889-94.
transparent image
78.   Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J. Inhibition of death receptor signals by cellular FLIP Nature 1997; 388:190-5.
transparent image
79.   Djerbi M, Screpanti V, Catrina AI, Bogen B, Biberfeld P, Grandien A, Dalens H, Rigal D, Djerbi R, Hadj Salah H, Belaid S, Achour H, Djerbi A, Mestiri S. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med 1999; 190:1025-32.
transparent image
80.   Swanton C, Mann DJ, Fleckenstein B, Neipel F, Peters G, Jones N. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature 1997; 390:184-7.
transparent image
81.   Chen J, Ueda K, Sakakibara S, Okuno T, Parravicini C, Corbellino M, Yamanishi K. Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator. Proc Natl Acad Sci U S A 2001; 98:4119-24.
transparent image
82.   Deng H, Chu JT, Rettig MB, Martinez-Maza O, Sun R. Rta of the human herpesvirus 8/Kaposi sarcoma-associated herpesvirus up- regulates human interleukin-6 gene expression. Blood 2002; 100:1919-21.
transparent image
83.   Gradoville L, Gerlach J, Grogan E, Shedd D, Nikiforow S, Metroka C, Miller G. Kaposi's sarcoma-associated herpesvirus open reading frame 50/Rta protein activates the entire viral lytic cycle in the HH-B2 primary effusion lymphoma cell line. J Virol 2000; 74:6207-12.
transparent image
84.   Samaniego F, Pati S, Karp JE, Prakash O, Bose D. Human herpesvirus 8 K1-associated nuclear factor-kappa B-dependent promoter activity: role in Kaposi's sarcoma inflammation? J Natl Cancer Inst Monogr 2001:15-23.
transparent image
85.   Sarid R, Sato T, Bohenzky RA, Russo JJ, Chang Y. Kaposi's sarcoma-associated herpesvirus encodes a functional bcl-2 homologue. Nat Med 1997; 3:293-8.
transparent image
86.   Friborg J, Jr., Kong WP, Flowers CC, Flowers SL, Sun Y, Foreman KE, Nickoloff BJ, Nabel GJ. Distinct biology of Kaposi's sarcoma-associated herpesvirus from primary lesions and body cavity lymphomas. J Virol 1998; 72:10073-82.
transparent image
87.   Dourmishev LA, Dourmishev AL, Palmeri D, Schwartz RA, Lukac DM. Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiol Mol Biol Rev 2003; 67:175-212, table of contents.
transparent image
88.   Jenner RG, Boshoff C. The molecular pathology of Kaposi's sarcoma-associated herpesvirus. Biochim Biophys Acta 2002; 1602:1-22.
transparent image
89.   Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, Sullivan L, Jenh CH, Narula SK, Chensue SW, Lira SA. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J Exp Med 2000; 191:445-54.
transparent image
90.   Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA, Gerhengorn MC. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998; 391:86-9.
transparent image
91.   Weindel K, Marme D, Weich HA. AIDS-associated Kaposi's sarcoma cells in culture express vascular endothelial growth factor. Biochem Biophys Res Commun 1992; 183:1167-74.
transparent image
92.   Foussat A, Wijdenes J, Bouchet L, Gaidano G, Neipel F, Balabanian K, Galanaud P, Couderc J, Emilie D. Human interleukin-6 is in vivo an autocrine growth factor for human herpesvirus-8-infected malignant B lymphocytes. Eur Cytokine Netw 1999; 10:501-8.
transparent image
93.   Burger R, Neipel F, Fleckenstein B, Savino R, Ciliberto G, Kalden JR, Gramatzki M. Human herpesvirus type 8 interleukin-6 homologue is functionally active on human myeloma cells. Blood 1998; 91:1858-63.
transparent image
94.   Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood 2000; 96:2069-73.
transparent image
95.   Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest 1990; 86:592-9.
transparent image
96.   Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B. Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 1994; 330:602-5.
transparent image
97.   Weber KS, Grone HJ, Rocken M, Klier C, Gu S, Wank R, Proudfoot AE, Nelson PJ, Weber C. Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II. Eur J Immunol 2001; 31:2458-66.
transparent image
98.   Lee BS, Alvarez X, Ishido S, Lackner AA, Jung JU. Inhibition of intracellular transport of B cell antigen receptor complexes by Kaposi's sarcoma-associated herpesvirus K1. J Exp Med 2000; 192:11-21.
transparent image
99.   Coscoy L, Ganem D. Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc Natl Acad Sci U S A 2000; 97:8051-6.
transparent image
100.   Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P. Biology of Kaposi's sarcoma. Eur J Cancer 2001; 37:1251-69.
transparent image
101.   Staskus KA, Zhong W, Gebhard K, Herndier B, Wang H, Renne R, Beneke J, Pudney J, Anderson DJ, Ganem D, Haase AT. Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 1997; 71:715-9.
transparent image
102.   Orenstein JM, Alkan S, Blauvelt A, Jeang KT, Weinstein MD, Ganem D, Herndier B. Visualization of human herpesvirus type 8 in Kaposi's sarcoma by light and transmission electron microscopy. Aids 1997; 11:F35-45.
transparent image
103.   Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, Hatzioannou T, Suggett FE, Aldam DM, Denton AS, et al. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma Lancet 1995; 346:799-802.
transparent image
104.   Moore PS, Kingsley LA, Holmberg SD, Spira T, Gupta P, Hoover DR, Parry JP, Conley LJ, Jaffe HW, Chang Y. Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma. Aids 1996; 10:175-80.
transparent image
105.   Pauk J, Huang ML, Brodie SJ, Wald A, Koelle DM, Schacker T, Celum C, Selke S, Corey L. Mucosal Shedding of Human Herpesvirus 8 in Men. N Engl J Med 2000; 343:1369-1377.
transparent image
106.   Monini P, de Lellis L, Fabris M, Rigolin F, Cassai E. Kaposi's sarcoma-associated herpesvirus DNA sequences in prostate tissue and human semen. N Engl J Med 1996; 334:1168-72.
transparent image
107.   Diamond C, Huang ML, Kedes DH, Speck C, Rankin GW, Jr., Ganem D, Coombs RW, Rose TM, Krieger JN, Corey L. Absence of detectable human herpesvirus 8 in the semen of human immunodeficiency virus-infected men without Kaposi's sarcoma. J Infect Dis 1997; 176:775-7.
transparent image
108.   Boldogh I, Szaniszlo P, Bresnahan WA, Flaitz CM, Nichols MC, Albrecht T. Kaposi's sarcoma herpesvirus-like DNA sequences in the saliva of individuals infected with human immunodeficiency virus. Clin Infect Dis 1996; 23:406-7.
transparent image
109.   Corey L, Brodie S, Huang ML, Koelle DM, Wald A. HHV-8 infection: a model for reactivation and transmission. Rev Med Virol 2002; 12:47-63.
transparent image
110.   Webster-Cyriaque J, Edwards RH, Quinlivan EB, Patton L, Wohl D, Raab-Traub N. Epstein-Barr virus and human herpesvirus 8 prevalence in human immunodeficiency virus-associated oral mucosal lesions. J Infect Dis 1997; 175:1324-32.
transparent image
111.   Vieira J, Huang ML, Koelle DM, Corey L. Transmissible Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in saliva of men with a history of Kaposi's sarcoma. J Virol 1997; 71:7083-7.
transparent image
112.   Goudsmit J, Renwick N, Dukers NH, Coutinho RA, Heisterkamp S, Bakker M, Schulz TF, Cornelissen M, Weverling GJ. Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997): analysis of seroconversions to ORF65 and ORF73. Proc Natl Acad Sci U S A 2000; 97:4838-43.
transparent image
113.  Casper C, Redman M, Huang ML, Taylor H, Pauk J, Lampinen T, Hawes SE, Ashley R, Corey L, Kiviat NB, Wald A. Predictors of Human Herpesvirus 8 (HHV-8) Oral Shedding Among Human Immunodeficiency Virus (HIV)Seropositive Men. J Acquir Immune Defic Syndr 2004; In Press.
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114.  Ghandi M, Ameli N, Bacchetti P, Greenspan J, Greenspan D, Navazesh M, Anastos K, Greenblatt R. Salivary HHV8 Shedding Is More Prevalent At Higher CD4 Counts, 40th Annual Meeting of the Infectious Disease Society of America, Chicago, IL., October 2002., 2002.
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115.   Cannon MJ, Dollard SC, Black JB, Edlin BR, Hannah C, Hogan SE, Patel MM, Jaffe HW, Offermann MK, Spira TJ, Pellett PE, Gunthel CJ. Risk factors for Kaposi's sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus. Aids 2003; 17:215-22.
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116.   Lorenzen T, Albrecht D, Paech V, Meyer T, Hoffmann C, Stoehr A, Degen O, Stellbrink HJ, Meigel WN, Arndt R, Plettenberg A. HHV-8 DNA in blood and the development of HIV-associated Kaposi's sarcoma in the era of HAART--a prospective evaluation. Eur J Med Res 2002; 7:283-6.
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117.   Smith MS, Bloomer C, Horvat R, Goldstein E, Casparian JM, Chandran B. Detection of human herpesvirus 8 DNA in Kaposi's sarcoma lesions and peripheral blood of human immunodeficiency virus-positive patients and correlation with serologic measurements. J Infect Dis 1997; 176:84-93.
transparent image
118.   Broccolo F, Bossolasco S, Careddu AM, Tambussi G, Lazzarin A, Cinque P. Detection of DNA of lymphotropic herpesviruses in plasma of human immunodeficiency virus-infected patients: frequency and clinical significance. Clin Diagn Lab Immunol 2002; 9:1222-8.
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119.   Engels EA, Biggar RJ, Marshall VA, Walters MA, Gamache CJ, Whitby D, Goedert JJ. Detection and quantification of Kaposi's sarcoma-associated herpesvirus to predict AIDS-associated Kaposi's sarcoma. Aids 2003; 17:1847-51.
transparent image
120.   Campbell TB, Borok M, Gwanzura L, MaWhinney S, White IE, Ndemera B, Gudza I, Fitzpatrick L, Schooley RT. Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage. Aids 2000; 14:2109-16.
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121.   Gill J, Bourboulia D, Wilkinson J, Hayes P, Cope A, Marcelin AG, Calvez V, Gotch F, Boshoff C, Gazzard B. Prospective study of the effects of antiretroviral therapy on kaposi sarcoma-associated herpesvirus infection in patients with and without kaposi sarcoma. J Acquir Immune Defic Syndr 2002; 31:384-90.
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122.   Rizzieri DA, Liu J, Traweek ST, Miralles GD. Clearance of HHV-8 from peripheral blood mononuclear cells with a protease inhibitor [letter]. Lancet 1997; 349:775-6.
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123.   Kedes DH, Ganem D. Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. J Clin Invest 1997; 99:2082-6.
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124.   Medveczky MM, Horvath E, Lund T, Medveczky PG. In vitro antiviral drug sensitivity of the Kaposi's sarcoma-associated herpesvirus. Aids 1997; 11:1327-32.
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125.   Zoeteweij JP, Eyes ST, Orenstein JM, Kawamura T, Wu L, Chandran B, Forghani B, Blauvelt A. Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents. J Virol 1999; 73:5894-902.
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126.   Ioannidis JP, Collier AC, Cooper DA, Corey L, Fiddian AP, Gazzard BG, Griffiths PD, Contopoulos-Ioannidis DG, Lau J, Pavia AT, Saag MS, Spruance SL, Youle MS. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis 1998; 178:349-59.
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127.   Glesby MJ, Hoover DR, Weng S, Graham NM, Phair JP, Detels R, Ho M, Saah AJ. Use of antiherpes drugs and the risk of Kaposi's sarcoma: data from the Multicenter AIDS Cohort Study. J Infect Dis 1996; 173:1477-80.
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128.   Martin DF, Kuppermann BD, Wolitz RA, Palestine AG, Li H, Robinson CA. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group. N Engl J Med 1999; 340:1063-70.
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129.   Robles R, Lugo D, Gee L, Jacobson MA. Effect of antiviral drugs used to treat cytomegalovirus end-organ disease on subsequent course of previously diagnosed Kaposi's sarcoma in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20:34-8.
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130.   Boivin G, Gaudreau A, Toma E, Lalonde R, Routy JP, Murray G, Handfield J, Bergeron MG. Human herpesvirus 8 DNA load in leukocytes of human immunodeficiency virus-infected subjects: correlation with the presence of Kaposi's sarcoma and response to anticytomegalovirus therapy. Antimicrob Agents Chemother 1999; 43:377-80.
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131.   Humphrey RW, O'Brien TR, Newcomb FM, Nishihara H, Wyvill KM, Ramos GA, Saville MW, Goedert JJ, Straus SE, Yarchoan R. Kaposi's sarcoma (KS)-associated herpesvirus-like DNA sequences in peripheral blood mononuclear cells: association with KS and persistence in patients receiving anti-herpesvirus drugs. Blood 1996; 88:297-301.
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132.   Mazzi R, Parisi SG, Sarmati L, Uccella I, Nicastri E, Carolo G, Gatti F, Concia E, Andreoni M. Efficacy of cidofovir on human herpesvirus 8 viraemia and Kaposi's sarcoma progression in two patients with AIDS. Aids 2001; 15:2061-2.
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133.   Little RF, Merced-Galindez F, Staskus K, Whitby D, Aoki Y, Humphrey R, Pluda JM, Marshall V, Walters M, Welles L, Rodriguez-Chavez IR, Pittaluga S, Tosato G, Yarchoan R. A pilot study of cidofovir in patients with kaposi sarcoma. J Infect Dis 2003; 187:149-53.
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134.   Low P, Neipel F, Rascu A, Steininger H, Manger B, Fleckenstein B, Kalden JR, Harrer T. Suppression of HHV-8 viremia by foscarnet in an HIV-infected patient with Kaposi's sarcoma and HHV-8 associated hemophagocytic syndrome. Eur J Med Res 1998; 3:461-4.
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135.   Luppi M, Barozzi P, Rasini V, Riva G, Re A, Rossi G, Setti G, Sandrini S, Facchetti F, Torelli G. Severe pancytopenia and hemophagocytosis after HHV-8 primary infection in a renal transplant patient successfully treated with foscarnet. Transplantation 2002; 74:131-2.
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136.   Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic syndrome with Kaposi's sarcoma- associated herpesvirus-related primary effusion lymphoma. Br J Haematol 2000; 111:1112-5.
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137.   Corbellino M, Bestetti G, Scalamogna C, Calattini S, Galazzi M, Meroni L, Manganaro D, Fasan M, Moroni M, Galli M, Parravicini C. Long-term remission of Kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy. Blood 2001; 98:3473-5.
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138.   Bottieau E, Colebunders R, Schroyens W, Van Droogenbroeck J, De Droogh E, Depraetere K, De Raeve H, Van Marck E. Multicentric Castleman's disease in 2 patients with HIV infection, unresponsive to antiviral therapy. Acta Clin Belg 2000; 55:97-101.
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139.   Casper C, Nichols WG, Huang ML, Corey L, Wald A. Remission of HHV-8 and HIV-associated multicentric Castleman's disease with ganciclovir treatment. Blood 2004; In press.
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140.   Gustafson EA, Schinazi RF, Fingeroth JD. Human herpesvirus 8 open reading frame 21 is a thymidine and thymidylate kinase of narrow substrate specificity that efficiently phosphorylates zidovudine but not ganciclovir. J Virol 2000; 74:684-92.
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141.   Lock MJ, Thorley N, Teo J, Emery VC. Azidodeoxythymidine and didehydrodeoxythymidine as inhibitors and substrates of the human herpesvirus 8 thymidine kinase. J Antimicrob Chemother 2002; 49:359-66.
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142.   Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS, Jr., Weichold FF. Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 2002; 99:3771-9.
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143.   Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, Palladino C, Leone P, Bugarini R, Malavasi L, Cafaro A, Falchi M, Valdembri D, Rezza G, Bussolino F, Monini P, Ensoli B. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 2002; 8:225-32.
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144.   Giddens WE, Jr., Tsai CC, Morton WR, Ochs HD, Knitter GH, Blakley GA. Retroperitoneal fibromatosis and acquired immunodeficiency syndrome in macaques. Pathologic observations and transmission studies. Am J Pathol 1985; 119:253-63.
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145.   Rose TM, Strand KB, Schultz ER, Schaefer G, Rankin GW, Jr., Thouless ME, Tsai CC, Bosch ML. Identification of two homologs of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in retroperitoneal fibromatosis of different macaque species. J Virol 1997; 71:4138-44.
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146.   Schultz ER, Rankin GW, Jr., Blanc MP, Raden BW, Tsai CC, Rose TM. Characterization of two divergent lineages of macaque rhadinoviruses related to Kaposi's sarcoma-associated herpesvirus. J Virol 2000; 74:4919-28.
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147.   Krown SE. Highly active antiretroviral therapy in AIDS-associated Kaposi's sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi's sarcoma. J Clin Oncol 2004; 22:399-402.
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