Human Immunodeficiency Virus

Viral Structure

HIV-1 has an almost 10-kb genome, which contains nine main genes encoding at least 15 viral proteins. Like all retroviruses, HIV-1 contains three key “structural” genes: (1) gag, which encodes the capsid, matrix, and nucleocapsid, and p6 proteins; (2) pol , which encodes the protease, reverse transcriptase, and integrase enzymes; and (3) env , which encodes the envelope proteins gp120 and gp41. HIV-1 has two essential “regulatory” genes ( tat and rev ) and four “accessory” genes ( vpr, vpu, vif , and nef ). The accessory genes are not absolutely required for viral replication but are important virulence factors in vivo.

Life Cycle

The mature HIV-1 virion is approximately 110 nm in diameter and is composed of a core surrounded by a lipid bilayer envelope. The virion core consists of a structural shell composed of a capsid protein. Within this shell are two copies of single-stranded positive-sense RNA, two transfer RNA primers of host cell origin, and multiple copies each of the virus-encoded reverse transcriptase, integrase, and RNAse H enzymes. Matrix protein surrounds the virion core and is associated with the transmembrane glycoprotein of the viral envelope (gp41). At least three more virus-encoded proteins (vpr, vif, and nef) are packaged within the virion. These proteins are active early in the intracellular life cycle of HIV-1 and contribute to the efficiency of infection. Trimers of an external glycoprotein (gp120), anchored by gp41, protrude from the lipid bilayer envelope. The gp120 glycoproteins contain binding sites for the cell surface HIV-1 receptor (CD4 molecule) and coreceptors (chemokine receptors) and therefore are functionally important in virus attachment and entry.

Virus–cell membrane fusion begins with the interaction of gp120 with the first immunoglobulin-like domain of the CD4 ⁺ molecule expressed on the cell surface. This interaction causes conformational changes in gp120 that allow binding of gp120 to the coreceptor. Binding results in exposure of a hydrophobic domain in gp41 that, in turn, leads to the insertion of this domain into the cell membrane and the initiation of viral envelope–cell membrane fusion.

After internalization and uncoating of the viral core, a new viral life cycle begins with the generation of a DNA transcript of viral RNA through the activity of the viral reverse transcriptase. As the linear, double-stranded DNA provirus is generated, it remains associated with RNA, matrix proteins, and the viral integrase enzyme as a preintegration complex. For completion of the viral replication cycle, the preintegration complex must be transported from the cytoplasm to the nucleus and integrated into host genomic DNA. The extent to which integration and subsequent virion synthesis occur appears to depend on the cell cycle stage and activation state of the infected cell. Cells with integrated provirus represent long-lived reservoirs for viral persistence and barriers to eradication of the virus from infected people.

The structural genes ( gag , pol , env ) encode precursor polyproteins that are cleaved to produce individual proteins. Virion assembly takes place primarily at the cell plasma membrane. As the virus buds through cellular membranes, it acquires a lipid bilayer along with viral envelope glycoproteins. Understanding of the viral life cycle has contributed to the development of antiretroviral agents that block viral entry or inhibit viral enzymes, including reverse transcriptase, protease, and integrase.

Early Infection Events

The CD4 molecule is the primary cellular receptor for HIV-1; cells that express this molecule on their cell surfaces (CD4 ⁺ T lymphocytes and cells of monocyte or macrophage lineage) are major targets for HIV-1 infection. Members of the chemokine receptor family are coreceptors for HIV. Cell surface chemokine receptors are 7-transmembrane, G-protein–coupled receptors that transduce chemokine binding into intracellular signals, which, in turn, lead to the activation and migration of leukocytes. The configuration of cysteine motifs in chemokines is the basis for structural groupings (C-C-C or CC-chemokines; C-X-C or CXC-chemokines) that determine differences in biologic activities. Most HIV-1 strains use the CCR5 or CXCR4 coreceptors.

CCR5 appears to be important especially in the initial establishment of infection. HIV-1 infection is uncommon in people with a homozygous 32-bp deletion in CCR5; their lymphocytes do not express this chemokine receptor on cell surfaces and are relatively resistant to infection with primary HIV-1 isolates in vitro. Nonetheless, several HIV-1–infected people who are homozygous for this defect have been identified, a finding suggesting that under some circumstances, other coreceptors could be used in the establishment of infection. Although heterozygosity for the CCR5 deletion mutant does not appear to protect from the acquisition of infection, studies in both adults and children indicate that it may protect against disease progression. Later in the course of infection, HIV often evolves to infect macrophages and CXCR4 ⁺ T lymphocytes, as the abundance of CCR5 ⁺ T cells becomes limiting.

Following virus entry, HIV-1 proteins interact with numerous cellular proteins to enhance virus replication. For example, Tat interacts with the cellular protein cyclin-T1 to increase the efficiency of proviral transcription; Gag interacts with tumor suppressor gene 101 to enhance virus budding from the plasma membrane; Vif helps prevent G to A hypermutation that can be induced by host-encoded cytidine deaminases; and Vpu inhibits Tetherin, which can otherwise prevent budding of HIV-1 from the plasma membrane.