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Molecular Insights Into HIV Biology
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Introduction
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Binding and Entry
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Cytoplasmic Events
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Crossing the Nuclear Pore
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Integration
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Transcriptional Controls
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Viral Transcripts
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HIV Replication
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Viral Assembly
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Virion Budding
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Summary and Conclusions
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Acknowledgements
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References
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Figures
Figure 1.Organization of the HIV Proviral Genome and Summary of Gene Product Functions
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Figure 2.Early Events Occurring After HIV Infection of a Susceptible Target Cell
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Figure 3.Mechanisms of Post-Integration Latency; Role of Tat
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Figure 4.Late Events in the HIV-Infected Cell Culminating in the Assembly of New Infectious Virions
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Figure 5.Late Steps in the Assembly of New Virions
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Introduction
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Bringing the global HIV epidemic under control will require more effective approaches to prevent the spread of the retrovirus, as well as broader use of existing and future antiretroviral drugs. These interventions must be applicable in the developing world, where HIV has the most severe impact. Understanding the dynamic interplay of HIV with its cellular host provides the biological basis for controlling the epidemic. This chapter reviews current understanding of the HIV life cycle, with particular attention to the interactions between viral proteins and cellular machinery, and highlights promising future points of attack.

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Binding and Entry
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The genetic material of HIV, an RNA molecule 9 kilobases in length, contains 9 different genes encoding 15 proteins. Considerable insights have been gained into the function of these different gene products.(Figure 1) To productively infect a target cell, HIV must introduce its genetic material into the cytoplasm of this cell. The process of viral entry involves fusion of the viral envelope with the host cell membrane and requires the specific interaction of the envelope with specific cell surface receptors. The two viral envelope proteins, gp120 and gp41, are conformationally associated to form a trimeric functional unit consisting of three molecules of gp120 exposed on the virion surface and associated with three molecules of gp41 inserted into the viral lipid membrane. Trimeric gp120 on the surface of the virion binds CD4 on the surface of the target cell, inducing a conformational change in the envelope proteins that in turn allows binding of the virion to a specific subset of chemokine receptors on the cell surface.(1)(Figure 2) These receptors normally play a role in chemoattraction, in which hematopoietic cells move along chemokine gradients to specific sites. Although these receptors, which contain seven membrane-spanning domains, normally transduce signals through G proteins,(2) signaling is not required for HIV infection.

Twelve chemokine receptors can function as HIV coreceptors in cultured cells, but only two are known to play a role in vivo.(2) One of these, CCR5, binds macrophage-tropic, non-syncytium-inducing (R5) viruses, which are associated with mucosal and intravenous transmission of HIV infection. The other, CXCR4, binds T-cell-tropic, syncytium-inducing (X4) viruses, which are frequently found during the later stages of disease.(3) In up to 13% of individuals of northern European descent, a naturally occurring deletion of 32 base pairs in the CCR5 gene results in a mutant CCR5 receptor that never reaches the cell surface.(4,5) Individuals homozygous for this mutation (1-2% of the Caucasian population) are almost completely resistant to HIV infection.(4,5) These observations emphasize the pivotal role of CCR5 in the spread of HIV and suggest that small molecules that prevent HIV interaction with CCR5 might form a promising new class of antiretroviral drugs.

Both CD4 and chemokine coreceptors for HIV are found disproportionately in lipid rafts in the cell membrane.(6) These cholesterol- and sphingolipid-enriched microdomains likely provide a better environment for membrane fusion, perhaps by mirroring the optimal lipid bilayer of the virus.(7) Removing cholesterol from virions, producer cells, or target cells greatly decreases the infectivity of HIV.(8) Studies currently under way are exploring whether cholesterol-depleting compounds might be efficacious as topically applied microbicides to inhibit HIV transmission at mucosal surfaces. The development of effective microbicides represents an important component of future HIV prevention strategies.

The binding of surface gp120, CD4, and the chemokine coreceptors produces an additional radical conformational change in gp41.(9) Assembled as a trimer on the virion membrane, this coiled-coil protein springs open, projecting three peptide fusion domains that "harpoon" the lipid bilayer of the target cell. The fusion domains then form hairpin-like structures that draw the virion and cell membranes together to promote fusion, leading to the release of the viral core into the cell interior.(9) The fusion inhibitors T-20 and T-1249 act to prevent fusion by blocking the formation of these hairpin structures.

HIV virions can also enter cells by endocytosis. Usually, productive infection does not result, presumably reflecting inactivation of these virions within endosomes. However, a special form of endocytosis has been demonstrated in submucosal dendritic cells. These cells, which normally process and present antigens to immune cells, express a specialized attachment structure termed DC-SIGN.(10) This C-type lectin binds HIV gp120 with high affinity but does not trigger the conformational changes required for fusion. Instead, virions bound to DC-SIGN are internalized into an acidic compartment and subsequently displayed on the cell surface after the dendritic cell has matured and migrated to regional lymph nodes, where it engages T cells.(11) Thus, dendritic cells expressing DC-SIGN appear to act as "Trojan horses" facilitating the spread of HIV from mucosal surfaces to T cells in lymphatic organs.

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Cytoplasmic Events
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Once inside the cell, the virion undergoes uncoating, likely while still associated with the plasma membrane.(Figure 2) This poorly understood process may involve phosphorylation of viral matrix proteins by a mitogen-activated protein (MAP) kinase(12) and additional actions of cyclophilin A(13) and the viral proteins Nef(14) and Vif.(15) Nef associates with a universal proton pump, V-ATPase,(16) which could promote uncoating by inducing local changes in pH in a manner similar to that of the M2 protein of influenza.(17) After the virion is uncoated, the viral reverse transcription complex is released from the plasma membrane.(18) This complex includes the diploid viral RNA genome, lysine transfer RNA (tRNALys) which acts as a primer for reverse transcription, viral reverse transcriptase, integrase, matrix and nucleocapsid proteins, viral protein R (Vpr), and various host proteins. The reverse transcription complex docks with actin microfilaments.(19) This interaction, mediated by the phosphorylated matrix, is required for efficient viral DNA synthesis. By overcoming destabilizing effects of a recently identified protein termed CEM15/APOBEC3G, Vif stabilizes the reverse transcription complex in most human cells.(15-20)

Reverse transcription yields the HIV preintegration complex (PIC), composed of double-stranded viral cDNA, integrase, matrix, Vpr, reverse transcriptase, and the high mobility group DNA-binding cellular protein HMGI(Y).(21) The PIC may move toward the nucleus by using microtubules as a conduit.(22) Adenovirus and herpes simplex virus 1 also dock with microtubules and use the microtubule-associated dynein molecular motor for cytoplasmic transport. This finding suggests that many viruses use these cytoskeletal structures for directional movement. How the switch from actin microfilaments to microtubules is orchestrated remains unknown.

Recent studies have revealed a mechanism by which the target cell defends against the HIV intruder.(23,24) Within 30 minutes of infection, select host proteins including the integrase interactor 1 (also known as INI-1, SNF5, or BAF47), a component of the SWI/SNF chromatin remodeling complex, and PML, a protein present in promyelocytic oncogenic domains, translocate from the nucleus into the cytoplasm.(24)(Figure 2) Addition of arsenic trioxide sharply blocks PML movement and enhances the susceptibility of cells to HIV infection raising the possibility that the normal function of PML is to oppose viral infection.(24) The binding of integrase to integrase interactor 1 may be a viral adaptation that recruits additional chromatin remodeling factors. Whether these complexes influence the site of viral integration or improve subsequent proviral gene expression is not known.

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Crossing the Nuclear Pore
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Unlike most animal retroviruses, HIV can infect nondividing cells, such as terminally differentiated macrophages.(25) This requires an ability to cross the intact nuclear membrane. With a Stokes radius of approximately 28 nm or roughly the size of a ribosome, the PIC is roughly twice as large as the maximal diameter of the central aqueous channel in the nuclear pore.(26) The 3 µm contour length of viral DNA must undergo significant compaction, and the import process must involve considerable molecular gymnastics.

One of the most contentious areas of HIV research involves the identification of key viral proteins that mediate the nuclear import of the PIC. Integrase,(27) matrix,(28) and Vpr(29) have been implicated.(Figure 2) Because plus-strand synthesis is discontinuous in reverse transcription, a triple helical DNA domain or "DNA flap" results that may bind a host protein containing a nuclear targeting signal.(30) Matrix contains a canonical nuclear localization signal that is recognized by the importins alpha and beta, which are components of the classical nuclear import pathway. However, a recent publication calls into question the contributions both of the nuclear import signal in integrase and of the DNA flap to the nuclear uptake of the PIC.(31) The HIV Vpr gene product contains at least three noncanonical nuclear targeting signals.(32) Vpr may bypass the importin system altogether, perhaps mediating the direct docking of the PIC with one or more components of the nuclear pore complex. The multiple nuclear targeting signals within the PIC may function in a cooperative manner or play larger roles individually in different target cells. For example, while Vpr is not needed for infection of nondividing, resting T cells,(33) it enhances viral infection in nondividing macrophages.(34) The finding that both matrix(35) and Vpr(32) shuttle between the nucleus and cytoplasm explains their availability for incorporation into new virions.

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Integration
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Once inside the nucleus, the viral PIC can establish a functional provirus.(Figure 2) Integration of double-stranded viral DNA into the host chromosome is mediated by integrase, which binds the ends of the viral DNA.(21) The host proteins HMGI(Y) and barrier to autointegration (BAF) are required for efficient integration, although their precise functions remain unknown.(36) Integrase removes terminal nucleotides from the viral DNA, producing a two-base recess and thereby correcting the ragged ends generated by the terminal transferase activity of reverse transcriptase.(21) Integrase also catalyzes the subsequent joining reaction that establishes the HIV provirus within the chromosome.

Not all PICs that enter the nucleus result in a functional provirus. The ends of the viral DNA may be joined to form a 2-LTR circle containing long terminal repeat sequences from both ends of the viral genome, or the viral genome may undergo homologous recombination yielding a single-LTR circle. Finally, the viral DNA may auto-integrate into itself, producing a rearranged circular structure. Although some circular forms may direct the synthesis of the transcriptional transactivator Tat or the accessory protein Nef, none produces infectious virus.(37) In a normal cellular response to DNA fragments, the nonhomologous end-joining (NHEJ) system may form 2-LTR circles to protect the cell.(38) This system is responsible for rapid repair of double-strand breaks, thereby preventing an apoptotic response. A single double-strand break within the cell can induce G1 cell-cycle arrest. The ability of the free ends of the viral DNA to mimic such double-strand chromosomal breaks may contribute to the direct cytopathic effects observed with HIV.

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Transcriptional Controls
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Integration can lead to latent or transcriptionally active forms of infection.(39) HIV's transcriptional latency explains the inability of potent antiviral therapies to eradicate the virus from the body. Moreover, despite a vigorous immune response early in infection, these silent proviruses are a reservoir that allows reemergence of HIV when the body's defenses grow weaker. Understanding latency and developing approaches to target latent virus are essential goals if eradication of HIV infection is ever to be achieved.

The chromosomal environment likely shapes the transcriptional activity of the provirus.(40) For example, proviral integration into repressed heterochromatin might result in latency.(Figure 3) Other causes of latency may include cell type differences in the availability of activators that bind to the transcriptional enhancer in the HIV LTR or the lack of Tat. However, of the multiple copies of provirus that are usually integrated in a given infected cell, at least one is likely to be transcriptionally active. This fact may explain why the number of latently infected cells (105-106) in infected patients is small.

In the host genome, the 5´ LTR functions like other eukaryotic transcriptional units. It contains downstream and upstream promoter elements, which include the initiator (Inr), TATA-box (T), and three Sp1 sites.(41) These regions help position the RNA polymerase II (RNAPII) at the site of initiation of transcription and to assemble the preinitiation complex. Slightly upstream of the promoter is the transcriptional enhancer, which in HIV-1 binds nuclear factor [kappa]B (NF-[kappa]B), nuclear factor of activated T cells (NFAT), and Ets family members.(42) NF-[kappa]B and NFAT relocalize to the nucleus after cellular activation. NF-[kappa]B is liberated from its cytoplasmic inhibitor, I[kappa]B, by stimulus-coupled phosphorylation, ubiquitination, and proteosomal degradation of the inhibitor.(43) NFAT is dephosphorylated by calcineurin (a reaction inhibited by cyclosporin A) and, after its nuclear import, assembles with AP1 to form the fully active transcriptional complex.(44) NF-[kappa]B, which is composed of p50 and p65 (RelA) subunits, increases the rates of initiation and elongation of viral transcription.(45) Since NF-[kappa]B is activated after several antigen-specific and cytokine-mediated events, it may play a key role in rousing transcriptionally silent proviruses

When these factors engage the LTR, transcription begins, but in the absence of Tat described below the polymerase fails to elongate efficiently along the viral genome.(Figure 3) In the process, short nonpolyadenylated transcripts are synthesized, which are stable and persist in cells due to the formation of an RNA stem loop called the transactivation response (TAR) element.(46)

Tat significantly increases the rate of viral gene expression. With cyclin T1 (CycT1), Tat binds to the TAR RNA stem-loop structure and recruits the cellular cyclin-dependent kinase 9 (Cdk9) to the HIV LTR.(47)(Figure 3) Within the positive transcription elongation factor b (P-TEFb) complex, Cdk9 phosphorylates the C-terminal domain of RNAPII, marking the transition from initiation to elongation of eukaryotic transcription.(48) Other targets of P-TEFb include negative transcription elongation factors (N-TEF), such as the DRB-sensitivity inducing (DSIF) and negative elongation (NELF) factors.(48) The high efficiency with which the HIV LTR attracts these negative transcription factors in vivo may explain why the LTR is a poor promoter in the absence of Tat. The arginine-rich motif (ARM) within Tat binds the 5´ bulge region in TAR. A shorter ARM in cyclin T1, which is also called the Tat-TAR recognition motif (TRM), binds the central loop of TAR.(47)

Binding of the Tat cyclin T1 complex to both the bulge and loop regions of TAR strengthens the affinity of this interaction. All of these components are required for Tat transactivation. In the presence of the complex between Tat and P-TEFb, the RNAPII elongates efficiently. Because murine CycT1 contains a cysteine at position 261, the complex between Tat and murine P-TEFb binds TAR weakly.(49) Thus, Tat transactivation is severely compromised in murine cells. Cdk9 also must undergo autophosphorylation of several serine and threonine residues near its C-terminus to allow productive interactions between Tat, P-TEFb, and TAR.(50) Additionally, basal levels of P-TEFb may be low in resting cells or only weakly active due to the interaction between P-TEFb and 7SK RNA.(51) All of these events may contribute to postintegration latency.

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Viral Transcripts
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Transcription of the viral genome results in more than a dozen different HIV-specific transcripts.(52) Some are processed cotranscriptionally and, in the absence of inhibitory RNA sequences (IRS), transported rapidly into the cytoplasm.(53) These multiply spliced transcripts encode Nef, Tat, and Rev. Other singly spliced or unspliced viral transcripts remain in the nucleus and are relatively stable. These viral transcripts encode the structural, enzymatic, and accessory proteins and represent viral genomic RNAs that are needed for the assembly of fully infectious virions.

Incomplete splicing likely results from suboptimal splice donor and acceptor sites in viral transcripts. In addition, the regulator of virion gene expression, Rev, may inhibit splicing by its interaction with alternate splicing factor/splicing factor 2 (ASF/SF2)(54) and its associated p32 protein.(55)

Transport of the incompletely spliced viral transcripts to the cytoplasm depends on an adequate supply of Rev.(53) Rev is a small shuttling protein that binds a complex RNA stem-loop termed the Rev response element (RRE), which is located in the env gene. Rev binds first with high affinity to a small region of the RRE termed the stem-loop IIB.(56)(Figure 4) This binding leads to the multimerization of Rev on the remainder of the RRE. In addition to a nuclear localization signal, Rev contains a leucine-rich nuclear export sequence (NES).(53) Of note, the study of Rev was the catalyst for the discovery of such NES in many cellular proteins and led to identification of the complex formed between CRM1/exportin-1 and this sequence.(53)

The nuclear export of this assembly (viral RNA transcript, Rev, and CRM1/exportin 1) depends critically on yet another host factor, RanGTP. Ran is a small guanine nucleotide-binding protein that switches between GTP- and GDP-bound states. RanGDP is found predominantly in the cytoplasm because the GTPase activating protein specific for Ran (RanGAP) is expressed in this cellular compartment. Conversely, the Ran nucleotide exchange factor, RCC1, which charges Ran with GTP, is expressed predominantly in the nucleus. The inverse nucleocytoplasmic gradients of RanGTP and RanGDP produced by the subcellular localization of these enzymes likely plays a major role in determining the directional transport of proteins into and out of the nucleus. Outbound cargo is only effectively loaded onto CRM1/exportin-1 in the presence of RanGTP. However, when the complex reaches the cytoplasm, GTP is hydrolyzed to GDP, resulting in release of the bound cargo. The opposite relationship regulates the nuclear import by importins alpha and beta, where nuclear RanGTP stimulates cargo release.(53)

For HIV infection to spread, a balance between splicing and transport of viral mRNA species must be achieved. If splicing is too efficient, then only the multiply spliced transcripts appear in the cytoplasm. Although required, the regulatory proteins encoded by multiply spliced transcripts are insufficient to support full viral replication. However, if splicing is impaired, adequate synthesis of Tat, Rev, and Nef will not occur. In many non-primate cells, HIV transcripts may be overly spliced, effectively preventing viral replication in these hosts.(57)

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HIV Replication
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In contrast to Tat and Rev, which act directly on viral RNA structures, Nef modifies the environment of the infected cell to optimize viral replication.(2)(Figure 4) The absence of Nef in infected monkeys and humans is associated with much slower clinical progression to AIDS.(58,59) This virulence caused by Nef appears to be associated with its ability to affect signaling cascades, including the activation of T-cell antigen receptor,(60) and to decrease the expression of CD4 on the cell surface.(61,62) Nef also promotes the production and release of virions that are more infectious.(63,64) Effects of Nef on the PI3-K signaling cascade--which involves the guanine nucleotide exchange factor Vav, the small GTPases Cdc42 and Rac1, and p21-activated kinase PAK--cause marked changes in the intracellular actin network, promoting lipid raft movement and the formation of larger raft structures that have been implicated in T-cell receptor signaling.(65) Indeed, Nef and viral structural proteins colocalize in lipid rafts.(64,66) Two other HIV proteins assist Nef in downregulating expression of CD4.(67) The envelope protein gp120 binds CD4 in the endoplasmic reticulum, slowing its export to the plasma membrane,(68) and Vpu binds the cytoplasmic tail of CD4, promoting recruitment of TrCP and Skp1p.(Figure 5) These events target CD4 for ubiquitination and proteasomal degradation before it reaches the cell surface.(69)

Nef acts by several mechanisms to impair immunological responses to HIV. In T cells, Nef activates the expression of FasL, which induces apoptosis in bystander cells that express Fas,(70) thereby killing cytotoxic T cells that might otherwise eliminate HIV-1 infected cells. Nef also reduces the expression of MHC I determinants on the surface of the infected cell(71)(Figure 4) and so decreases the recognition and killing of infected cells by CD8 cytotoxic T cells. However, Nef does not decrease the expression of HLA-C,(72) which prevents recognition and killing of these infected cells by natural killer cells.

Nef also inhibits apoptosis. It binds and inhibits the intermediate apoptosis signal regulating kinase-1 (ASK-1)(73) that functions in the Fas and TNFR death signaling pathways and stimulates the phosphorylation of Bad leading to its sequestration by 14-3-3 proteins.(74)(Figure 4) Nef also binds the tumor suppressor protein p53, inhibiting another potiential initator of apoptosis.(75) Via these different mechanisms, Nef prolongs the life of the infected host cell, thereby optimizing viral replication.

Other viral proteins also participate in the modification of the environment in infected cells. Rev-dependent expression of Vpr induces the arrest of proliferating infected cells at the G2/M phase of the cell cycle.(76) Since the viral LTR is more active during G2, this arrest likely enhances viral gene expression.(77) These cell-cycle arresting properties involve localized defects in the structure of the nuclear lamina that lead to dynamic, DNA-filled herniations that project from the nuclear envelope into the cytoplasm.(78)(Figure 4) Intermittently, these herniations rupture, causing the mixing of soluble nuclear and cytoplasmic proteins. Either alterations in the lamina structure or the inappropriate mixing of cell cycle regulators that are normally sequestered in specific cellular compartments could explain the G2 arresting properties of Vpr.

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Viral Assembly
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New viral particles are assembled at the plasma membrane.(Figure 5) Each virion consists of roughly 1500 molecules of Gag and 100 Gag-Pol polyproteins,(79) two copies of the viral RNA genome, and Vpr.(80) Several proteins participate in the assembly process, including Gag polyproteins and Gag-Pol, as well as Nef and Env. A human ATP-binding protein, HP68 (previously identified as an RNase L inhibitor), likely acts as a molecular chaperone, facilitating conformational changes in Gag needed for the assembly of viral capsids.(81) In primary CD4 T lymphocytes, Vif plays a key but poorly understood role in the assembly of infectious virions. In the absence of Vif, normal levels of virus are produced, but these virions are noninfectious, displaying arrest at the level of reverse transcription in the subsequent target cell. Heterokaryon analyses of cells formed by the fusion of nonpermissive (requiring Vif for viral growth) and permissive (supporting growth of Vif-deficient viruses) cells have revealed that Vif overcomes the effects of a natural inhibitor of HIV replication.(20,82) Recently this factor, initially termed CEM15/APOBEC3G, was identified(83) and shown to share homology with APOBEC1, an enzyme involved in RNA editing. Whether the intrinsic antiviral activity of CEM15 involves such an RNA editing function remains unknown. CEM15 is expressed in non-permissive but not in permissive cells and when introduced alone is sufficient to render permissive cells nonpermissive.

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Virion Budding
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The Gag polyproteins are subject to myristylation,(84) and thus associate preferentially with cholesterol- and glycolipid-enriched membrane microdomains.(85) Virion budding occurs through these specialized regions in the lipid bilayer, yielding virions with cholesterol-rich membranes. This lipid composition likely favors release, stability, and fusion of virions with the subsequent target cell.(7)

The budding reaction involves the action of several proteins, including the "late domain"(86) sequence (PTAP) present in the p6 portion of Gag.(87)(Figure 5) The p6 protein also appears to be modified by ubiquitination. The product of the tumor suppressor gene 101 (TSG101) binds the PTAP motif of p6 Gag and also recognizes ubiquitin through its ubiquitin enzyme 2 (UEV) domain.(88,89) The TSG101 protein normally associates with other cellular proteins in the vacuolar protein sorting pathway to form the ESCRT-1 complex that selects cargo for incorporation into the multivesicular body (MVB).(90) The MVB is produced when surface patches on late endosomes bud away from the cytoplasm and fuse with lysosomes, releasing their contents for degradation within this organelle. In the case of HIV, TSG101 appears to be "hijacked" to participate in the budding of virions into the extracellular space away from the cytoplasm.

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Summary and Conclusions
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As the AIDS pandemic continues, advances in antiretroviral therapies have slowed its advance in the industrialized world, but have had little effect in developing countries. Because of its high rate of mutation, HIV is able to refine and optimize its interactions with various host proteins and pathways, thereby promoting its growth and spread. The virus ensures that the host cell survives until the viral replicative cycle is completed. Possibly even more damaging, HIV establishes stable latent forms that support the chronic nature of infection. Eradication of the virus appears unlikely until effective methods are developed to purge these latent viral reservoirs.

Basic science will clearly play a leading role in future attempts to solve the mysteries of viral latency and replication. A small-animal model that recapitulates the pathogenic mechanisms of HIV is sorely needed to study the mechanisms underlying viral cytopathogenesis. Virally induced cell death is not limited to infected targets but also involves uninfected bystander cells.(91) Murine cells support neither efficient virion assembly nor release of virions from the cell surface.(92) Currently, this defect represents a major impediment to the successful development of a rodent model of AIDS.

Proposed mechanisms for HIV killing of T cells include the formation of giant cell syncytia through the interactions of gp120 with CD4 and chemokine receptors,(93) the accumulation of unintegrated linear forms of viral DNA, the proapoptotic effects of the Tat,(94) Nef,(95) and Vpr(96) proteins, and the adverse effects conferred by the metabolic burden that HIV replication places on the infected cell.(97) Of note, expression of Nef alone as a transgene in mice recapitulates many of the clinical features of AIDS, including immunodeficiency and loss of CD4-positive cells.(98) All of these mechanisms suggest potential points of therapeutic intervention. Finally, future therapies will likely target viral proteins other than the reverse transcriptase, protease, and integrase enzymes. Clinical trials are already underway to study small molecules or short peptides that block the binding of HIV to cell-surface chemokine receptors or interfere with the machinery of viral-host cell fusion. Although not as advanced in development, small molecules have been found that block Tat transactivation(99) and Rev-dependent export of viral transcripts from the nucleus to the cytoplasm.(100) As a proof of principle, dominant-negative mutants of Tat, Rev, and Gag proteins have been shown to block viral replication. By increasing the number of antiviral compounds available to target different steps in the viral replicative cycle, in particular drugs that can be deployed in developing countries, research at the cellular level can serve to extend survival and to improve the quality of life for infected individuals, and to inhibit the spread of AIDS.

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Acknowledgements
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Warner C. Greene thanks Gary Howard and Stephen Ordway for editorial support, Robin Givens for administrative support, and the National Institutes of Health (R01 AI45234-02, R01 CA86814-02, P01 HD40543), the UCSF California AIDS Research Center (C99-SF-002), the James B. Pendleton Charitable Trust, and the J. David Gladstone Institutes for funding support.

B. Matija Peterlin thanks the National Institutes of Health (R01-AI38532, R01-AI46967, RO1-AI49104, and R01-AI51165-01) and the Universitywide AIDS Research Program (R00-SF-006) for funding support.

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References

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1.   Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998 Jun 18;393(6686):648-59.
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2.   Doms RW, Trono D. The plasma membrane as a combat zone in the HIV battlefield. Genes Dev. 2000 Nov 1;14(21):2677-88.
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3.   Scarlatti G, Tresoldi E, Bjorndal A, Fredriksson R, Colognesi C, Deng HK, Malnati MS, Plebani A, Siccardi AG, Littman DR, Fenyo EM, Lusso P. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nat Med. 1997 Nov;3(11):1259-65.
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4.   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 Aug 9;86(3):367-77.
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5.   Martinson JJ, Chapman NH, Rees DC, Liu YT, Clegg JB. Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet. 1997 May;16(1):100-3.
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6.   Kozak SL, Heard JM, Kabat D. Segregation of CD4 and CXCR4 into distinct lipid microdomains in T lymphocytes suggests a mechanism for membrane destabilization by human immunodeficiency virus. J Virol. 2002 Feb;76(4):1802-15.
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7.   Campbell SM, Crowe SM, Mak J. Lipid rafts and HIV-1: from viral entry to assembly of progeny virions. J Clin Virol. 2001 Oct;22(3):217-27.
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8.   Liao Z, Cimakasky LM, Hampton R, Nguyen DH, Hildreth JE. Lipid rafts and HIV pathogenesis: host membrane cholesterol is required for infection by HIV type 1. AIDS Res Hum Retroviruses. 2001 Jul 20;17(11):1009-19.
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9.   Chan DC, Kim PS. HIV entry and its inhibition. Cell. 1998 May 29;93(5):681-4.
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10.   Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR, Figdor CG, van Kooyk Y. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 2000 Mar 3;100(5):587-97.
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11.   Kwon DS, Gregorio G, Bitton N, Hendrickson WA, Littman DR. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity. 2002 Jan;16(1):135-44.
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12.   Cartier C, Sivard P, Tranchat C, Decimo D, Desgranges C, Boyer V. Identification of three major phosphorylation sites within HIV-1 capsid. Role of phosphorylation during the early steps of infection. J Biol Chem. 1999 Jul 2;274(27):19434-40.
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13.   Franke EK, Yuan HE, Luban J. Specific incorporation of cyclophilin A into HIV-1 virions. Nature. 1994 Nov 24;372(6504):359-62.
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14.   Schaeffer E, Geleziunas R, Greene WC. Human immunodeficiency virus type 1 Nef functions at the level of virus entry by enhancing cytoplasmic delivery of virions. J Virol. 2001 Mar;75(6):2993-3000.
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15.   Ohagen A, Gabuzda D. Role of Vif in stability of the human immunodeficiency virus type 1 core. J Virol. 2000 Dec;74(23):11055-66.
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16.   Lu X, Yu H, Liu SH, Brodsky FM, Peterlin BM. Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4. Immunity. 1998 May;8(5):647-56.
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17.   Takeda M, Pekosz A, Shuck K, Pinto LH, Lamb RA. Influenza a virus M2 ion channel activity is essential for efficient replication in tissue culture. J Virol. 2002 Feb;76(3):1391-9.
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18.   Karageorgos L, Li P, Burrell C. Characterization of HIV replication complexes early after cell-to-cell infection. AIDS Res Hum Retroviruses. 1993 Sep;9(9):817-23.
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19.   Bukrinskaya A, Brichacek B, Mann A, Stevenson M. Establishment of a functional human immunodeficiency virus type 1 (HIV-1) reverse transcription complex involves the cytoskeleton. J Exp Med. 1998 Dec 7;188(11):2113-25.
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20.   Simon JH, Gaddis NC, Fouchier RA, Malim MH. Evidence for a newly discovered cellular anti-HIV-1 phenotype. Nat Med. 1998 Dec;4(12):1397-400.
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21.   Miller MD, Farnet CM, Bushman FD. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol. 1997 Jul;71(7):5382-90.
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22.   McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG, Emerman M, Hope TJ. Visualization of the intracellular behavior of HIV in living cells. J Cell Biol. 2002 Nov 11;159(3):441-52.
transparent image
23.   Bell P, Montaner LJ, Maul GG. Accumulation and intranuclear distribution of unintegrated human immunodeficiency virus type 1 DNA. J Virol. 2001 Aug;75(16):7683-91.
transparent image
24.   Turelli P, Doucas V, Craig E, Mangeat B, Klages N, Evans R, Kalpana G, Trono D. Cytoplasmic recruitment of INI1 and PML on incoming HIV preintegration complexes: interference with early steps of viral replication. Mol Cell. 2001 Jun;7(6):1245-54.
transparent image
25.   Weinberg JB, Matthews TJ, Cullen BR, Malim MH. Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J Exp Med. 1991 Dec 1;174(6):1477-82.
transparent image
26.   Pemberton LF, Blobel G, Rosenblum JS. Transport routes through the nuclear pore complex. Curr Opin Cell Biol. 1998 Jun;10(3):392-9.
transparent image
27.   Gallay P, Hope T, Chin D, Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc Natl Acad Sci USA. 1997 Sep 2;94(18):9825-30.
transparent image
28.   Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A, Spitz L, Lewis P, Goldfarb D, Emerman M, Stevenson M. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature. 1993 Oct 14;365(6447):666-9.
transparent image
29.   Heinzinger NK, Bukinsky MI, Haggerty SA, Ragland AM, Kewalramani V, Lee MA, Gendelman HE, Ratner L, Stevenson M, Emerman M. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci USA. 1994 Jul 19;91(15):7311-5.
transparent image
30.   Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P. HIV-1 genome nuclear import is mediated by a central DNA flap. Cell. 2000 Apr 14;101(2):173-85.
transparent image
31.   Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH. Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. J Virol. 2002 Dec;76(23):12087-96.
transparent image
32.   Sherman MP, de Noronha CM, Heusch MI, Greene S, Greene WC. Nucleocytoplasmic shuttling by human immunodeficiency virus type 1 Vpr. J Virol. 2001 Feb;75(3):1522-32.
transparent image
33.   Eckstein DA, Sherman MP, Penn ML, Chin PS, De Noronha CM, Greene WC, Goldsmith MA. HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells. J Exp Med. 2001 Nov 19;194(10):1407-19.
transparent image
34.   Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev. 1998 Jan 15;12(2):175-85.
transparent image
35.   Dupont S, Sharova N, DeHoratius C, Virbasius CM, Zhu X, Bukrinskaya AG, Stevenson M, Green MR. A novel nuclear export activity in HIV-1 matrix protein required for viral replication. Nature. 1999 Dec 9;402(6762):681-5.
transparent image
36.   Chen H, Engelman A. The barrier-to-autointegration protein is a host factor for HIV type 1 integration. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15270-4.
transparent image
37.   Wu Y, Marsh JW. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science. 2001 Aug 24;293(5534):1503-6.
transparent image
38.   Li L, Olvera JM, Yoder KE, Mitchell RS, Butler SL, Lieber M, Martin SL, Bushman FD. Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection. EMBO J. 2001 Jun 15;20(12):3272-81.
transparent image
39.   Adams M, Sharmeen L, Kimpton J, Romeo JM, Garcia JV, Peterlin BM, Groudine M, Emerman M. Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3862-6.
transparent image
40.   Jordan A, Defechereux P, Verdin E. The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. EMBO J. 2001 Apr 2;20(7):1726-38.
transparent image
41.   Taube R, Fujinaga K, Wimmer J, Barboric M, Peterlin BM. Tat transactivation: a model for the regulation of eukaryotic transcriptional elongation. Virology. 1999 Nov 25;264(2):245-53
transparent image
42.   Jones KA, Peterlin BM. Control of RNA initiation and elongation at the HIV-1 promoter. Annu Rev Biochem. 1994;63:717-43.
transparent image
43.   Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621-63.
transparent image
44.   Crabtree GR. Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT. Cell. 1999 Mar 5;96(5):611-4.
transparent image
45.   Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001 Aug;8(2):327-37.
transparent image
46.   Kao SY, Calman AF, Luciw PA, Peterlin BM. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature. 1987 Dec 3-9;330(6147):489-93.
transparent image
47.   Wei P, Garber ME, Fang SM, Fischer WH, Jones KA. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell. 1998 Feb 20;92(4):451-62.
transparent image
48.   Price DH. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol. 2000 Apr;20(8):2629-34.
transparent image
49.   Garber ME, Wei P, KewalRamani VN, Mayall TP, Herrmann CH, Rice AP, Littman DR, Jones KA. The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Genes Dev. 1998 Nov 15;12(22):3512-27.
transparent image
50.   Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Mol Cell Biol. 2000 Sep;20(18):6958-69.
transparent image
51.   Yang Z, Zhu Q, Luo K, Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature. 2001 Nov 15;414(6861):317-22.
transparent image
52.   Saltarelli MJ, Hadziyannis E, Hart CE, Harrison JV, Felber BK, Spira TJ, Pavlakis GN. Analysis of human immunodeficiency virus type 1 mRNA splicing patterns during disease progression in peripheral blood mononuclear cells from infected individuals. AIDS Res Hum Retroviruses. 1996 Oct 10;12(15):1443-56.
transparent image
53.   Cullen BR. Retroviruses as model systems for the study of nuclear RNA export pathways. Virology. 1998 Sep 30;249(2):203-10.
transparent image
54.   Powell DM, Amaral MC, Wu JY, Maniatis T, Greene WC. HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing. Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):973-8.
transparent image
55.   Luo Y, Yu H, Peterlin BM. Cellular protein modulates effects of human immunodeficiency virus type 1 Rev. J Virol. 1994 Jun;68(6):3850-6.
transparent image
56.   Malim MH, Tiley LS, McCarn DF, Rusche JR, Hauber J, Cullen BR. HIV-1 structural gene expression requires binding of the Rev trans-activator to its RNA target sequence. Cell. 1990 Feb 23;60(4):675-83.
transparent image
57.   Malim MH, Cullen BR. Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes. Mol Cell Biol. 1993 Oct;13(10):6180-9.
transparent image
58.   Kestler HW 3rd, Ringler DJ, Mori K, Panicali DL, Sehgal PK, Daniel MD, Desrosiers RC. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell. 1991 May 17;65(4):651-62.
transparent image
59.   Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C, et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science. 1995 Nov 10;270(5238):988-91.
transparent image
60.   Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77.
transparent image
61.   Khan IH, Sawai ET, Antonio E, Weber CJ, Mandell CP, Montbriand P, Luciw PA. Role of the SH3-ligand domain of simian immunodeficiency virus Nef in interaction with Nef-associated kinase and simian AIDS in rhesus macaques. J Virol. 1998 Jul;72(7):5820-30.
transparent image
62.   Glushakova S, Munch J, Carl S, Greenough TC, Sullivan JL, Margolis L, Kirchhoff F. CD4 down-modulation by human immunodeficiency virus type 1 Nef correlates with the efficiency of viral replication and with CD4(+) T-cell depletion in human lymphoid tissue ex vivo. J Virol. 2001 Nov;75(21):10113-7.
transparent image
63.   Lama J, Mangasarian A, Trono D. Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner. Curr Biol. 1999 Jun 17;9(12):622-31.
transparent image
64.   Zheng YH, Plemenitas A, Linnemann T, Fackler OT, Peterlin BM. Nef increases infectivity of HIV via lipid rafts. Curr Biol. 2001 Jun 5;11(11):875-9.
transparent image
65.   Geyer M, Fackler OT, Peterlin BM. Structure--function relationships in HIV-1 Nef. EMBO Rep. 2001 Jul;2(7):580-5.
transparent image
66.   JK, Kiyokawa E, Verdin E, Trono D. The Nef protein of HIV-1 associates with rafts and primes T cells for activation. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):394-9.
transparent image
67.   Chen BK, Gandhi RT, Baltimore D. CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef. J Virol. 1996 Sep;70(9):6044-53.
transparent image
68.   Crise B, Buonocore L, Rose JK. CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor. J Virol. 1990 Nov;64(11):5585-93.
transparent image
69.   Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R. A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell. 1998 Mar;1(4):565-74.
transparent image
70.   Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ, Baur AS. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med. 1999 May 3;189(9):1489-96.
transparent image
71.   Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature. 1998 Jan 22;391(6665):397-401.
transparent image
72.   Le Gall S, Erdtmann L, Benichou S, Berlioz-Torrent C, Liu L, Benarous R, Heard JM, Schwartz O. Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules. Immunity. 1998 Apr;8(4):483-95.
transparent image
73.   Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature. 2001 Apr 12;410(6830):834-8.
transparent image
74.   Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S, d'Aloja P, Schurmann A, Baur AS. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001 Nov;7(11):1217-24.
transparent image
75.   Greenway AL, McPhee DA, Allen K, Johnstone R, Holloway G, Mills J, Azad A, Sankovich S, Lambert P. Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. J Virol. 2002 Mar;76(6):2692-702.
transparent image
76.   Jowett JB, Planelles V, Poon B, Shah NP, Chen ML, Chen IS. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol. 1995 Oct;69(10):6304-13.
transparent image
77.   Goh WC, Rogel ME, Kinsey CM, Michael SF, Fultz PN, Nowak MA, Hahn BH, Emerman M. HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat Med. 1998 Jan;4(1):65-71.
transparent image
78.   de Noronha CM, Sherman MP, Lin HW, Cavrois MV, Moir RD, Goldman RD, Greene WC. Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science. 2001 Nov 2;294(5544):1105-8.
transparent image
79.   Wilk T, Gross I, Gowen BE, Rutten T, de Haas F, Welker R, Krausslich HG, Boulanger P, Fuller SD. Organization of immature human immunodeficiency virus type 1. J Virol. 2001 Jan;75(2):759-71.
transparent image
80.   Freed EO. HIV-1 gag proteins: diverse functions in the virus life cycle. Virology. 1998 Nov 10;251(1):1-15.
transparent image
81.   Zimmerman C, Klein KC, Kiser PK, Singh AR, Firestein BL, Riba SC, Lingappa JR. Identification of a host protein essential for assembly of immature HIV-1 capsids. Nature. 2002 Jan 3;415(6867):88-92.
transparent image
82.   Madani N, Kabat D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein. J Virol. 1998 Dec;72(12):10251-5.
transparent image
83.   Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002 Aug 8;418(6898):646-50.
transparent image
84.   Gottlinger HG, Sodroski JG, Haseltine WA. Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of human immunodeficiency virus type 1. Proc Natl Acad Sci USA. 1989 Aug;86(15):5781-5.
transparent image
85.   Ono A, Freed EO. Plasma membrane rafts play a critical role in HIV-1 assembly and release.Proc Natl Acad Sci USA. 2001 Nov 20;98(24):13925-30.
transparent image
86.   Garnier L, Parent LJ, Rovinski B, Cao SX, Wills JW. Identification of retroviral late domains as determinants of particle size. J Virol. 1999 Mar;73(3):2309-20.
transparent image
87.   Strack B, Calistri A, Accola MA, Palu G, Gottlinger HG. A role for ubiquitin ligase recruitment in retrovirus release. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13063-8.
transparent image
88.   Garrus JE, von Schwedler UK, Pornillos OW, Morham SG, Zavitz KH, Wang HE, Wettstein DA, Stray KM, Cote M, Rich RL, Myszka DG, Sundquist WI. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell. 2001 Oct 5;107(1):55-65.
transparent image
89.   VerPlank L, Bouamr F, LaGrassa TJ, Agresta B, Kikonyogo A, Leis J, Carter CA. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag). Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7724-9.
transparent image
90.   Katzmann DJ, Babst M, Emr SD. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell. 2001 Jul 27;106(2):145-55.
transparent image
91.   Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med. 1995 Feb;1(2):129-34.
transparent image
92.   Bieniasz PD, Cullen BR. Multiple blocks to human immunodeficiency virus type 1 replication in rodent cells. J Virol. 2000 Nov;74(21):9868-77.
transparent image
93.   Kowalski M, Potz J, Basiripour L, Dorfman T, Goh WC, Terwilliger E, Dayton A, Rosen C, Haseltine W, Sodroski J. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science. 1987 Sep 11;237(4820):1351-5.
transparent image
94.   Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature. 1995 Jun 8;375(6531):497-500.
transparent image
95.   Baur AS, Sawai ET, Dazin P, Fantl WJ, Cheng-Mayer C, Peterlin BM. HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. Immunity. 1994 Aug;1(5):373-84.
transparent image
96.   Stewart SA, Poon B, Jowett JB, Chen IS. Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest. J Virol. 1997 Jul;71(7):5579-92.
transparent image
97.   Somasundaran M, Robinson HL. Unexpectedly high levels of HIV-1 RNA and protein synthesis in a cytocidal infection. Science. 1988 Dec 16;242(4885):1554-7.
transparent image
98.   Hanna Z, Kay DG, Rebai N, Guimond A, Jothy S, Jolicoeur P. Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell. 1998 Oct 16;95(2):163-75.
transparent image
99.   Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM, Price DH. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.J Biol Chem. 2000 Sep 15;275(37):28345-8.
transparent image
100.   Wolff B, Sanglier JJ, Wang Y. Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol. 1997 Feb;4(2):139-47.
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