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