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Published by: odin3z on Mar 22, 2010
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Molecular Insights Into HIV BiologyIntroduction
Bringing the global HIV epidemic under control will require more effective approaches to prevent thespread of the retrovirus, as well as broader use of existing and future antiretroviral drugs. Theseinterventions 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 futurepoints of attack.
Binding and Entry
The genetic material of HIV, an RNA molecule 9 kilobases in length, contains 9 different genes encoding15 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 andrequires the specific interaction of the envelope with specific cell surface receptors. The two viralenvelope proteins, gp120 and gp41, are conformationally associated to form a trimeric functional unitconsisting of three molecules of gp120 exposed on the virion surface and associated with three moleculesof gp41 inserted into the viral lipid membrane. Trimeric gp120 on the surface of the virion binds CD4 onthe surface of the target cell, inducing a conformational change in the envelope proteins that in turn allowsbinding 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 chemokinegradients 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 toplay 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 occurringdeletion of 32 base pairs in the CCR5 gene results in a mutant CCR5 receptor that never reaches the cellsurface.(4,5) Individuals homozygous for this mutation (1-2% of the Caucasian population) are almostcompletely resistant to HIV infection.(4,5) These observations emphasize the pivotal role of CCR5 in thespread 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 cellmembrane.(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) Removingcholesterol from virions, producer cells, or target cells greatly decreases the infectivity of HIV.(8) Studiescurrently under way are exploring whether cholesterol-depleting compounds might be efficacious astopically 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 radicalconformational change in gp41.(9) Assembled as a trimer on the virion membrane, this coiled-coil proteinsprings 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 topromote 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, presumablyreflecting inactivation of these virions within endosomes. However, a special form of endocytosis hasbeen demonstrated in submucosal dendritic cells. These cells, which normally process and presentantigens 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 subsequentlydisplayed 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.
Cytoplasmic Events
Once inside the cell, the virion undergoes uncoating, likely while still associated with the plasmamembrane.(Figure 2) This poorly understood process may involve phosphorylation of viral matrix proteinsby 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 theplasma membrane.(18) This complex includes the diploid viral RNA genome, lysine transfer RNA(tRNA
) 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 transcriptioncomplex docks with actin microfilaments.(19) This interaction, mediated by the phosphorylated matrix, isrequired for efficient viral DNA synthesis. By overcoming destabilizing effects of a recently identifiedprotein 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 viralcDNA, 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-associateddynein molecular motor for cytoplasmic transport. This finding suggests that many viruses use thesecytoskeletal structures for directional movement. How the switch from actin microfilaments tomicrotubules 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 (alsoknown as INI-1, SNF5, or BAF47), a component of the SWI/SNF chromatin remodeling complex, andPML, a protein present in promyelocytic oncogenic domains, translocate from the nucleus into thecytoplasm.(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 opposeviral 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.
Crossing the Nuclear Pore
Unlike most animal retroviruses, HIV can infect nondividing cells, such as terminally differentiatedmacrophages.(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 maximaldiameter of the central aqueous channel in the nuclear pore.(26) The 3 µm contour length of viral DNAmust 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 thatmediate 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 DNAdomain or "DNA flap" results that may bind a host protein containing a nuclear targeting signal.(30) Matrix

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