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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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