HIV is a retrovirus, a member of the Lentivirus genus, and exhibits many of the physicochemical features typical of the family. The unique morphologic characteristic of HIV is a cylindrical nucleoid in the mature virion (Figure 1). The diagnostic bar-shaped nucleoid is visible in electron micrographs in those extracellular particles that happen to be sectioned at the appropriate angle.
Fig1. Electron micrographs of HIV-infected lymphocytes, showing a large accumulation of freshly produced virus at the cell surface (top, 46,450×, bar = 100 nm); newly formed virus budding from cytoplasmic membrane (lower left, 49,000×, bar = 100 nm); and two virions about to be cast off from cell surface (lower right, 75,140×, bar = 100 nm).
The RNA genome of lentiviruses is more complex than that of transforming retroviruses (Figure 2). Lentiviruses contain the four genes required for a replicating retrovirus— gag, pro, pol, and env—and follow the general pattern for retrovirus replication. Up to six additional genes regulate viral expression and are important in disease pathogenesis in vivo. Although these auxiliary genes show little sequence homology among lentiviruses, their functions are conserved. (The feline and ungulate viruses encode fewer accessory genes.) One early-phase replication protein, the Tat protein, functions in “transactivation,” whereby a viral gene product is involved in transcriptional activation of other viral genes. Transactivation by HIV is highly efficient and may contribute to the virulent nature of HIV infections. The Rev protein is required for the expression of viral structural proteins. Rev facilitates the export of unspliced viral transcripts from the nucleus; structural proteins are translated from unspliced mRNAs during the late phase of viral replication. The Nef protein increases viral infectivity, facilitates activation of resting T cells, and downregulates expression of CD4 and MHC class I. The nef gene is necessary for simian immunodeficiency virus (SIV) to be pathogenic in monkeys. The Vpr protein increases transport of the viral preintegration complex into the nucleus and also arrests cells in the G2 phase of the cell cycle. The Vpu protein promotes CD4 degradation.
Fig2. HIV genome and virion structure. The HIV-1 genome is shown at the top. Viral proteins are synthesized as precursor polyproteins (Gag-Pol [Pr160], Gag [Pr55], and Env [gp160]), which are enzymatically processed to yield mature virion proteins. Gag-Pol and Gag are cleaved by the viral protease PR to produce the indicated smaller proteins. Env is cleaved by a cellular PR, producing SU gp120 and TM gp41. The placements of virion proteins in the virus particle are indicated by symbols (bottom of figure). HIV-2 and SIV lack the vpu gene but contain a vpx gene. (Reproduced from Peterlin BM: Molecular biology of HIV. In Levy JA [editor]. The Viruses. Vol 4: The Retroviridae. Plenum, 1995. Modified there from Luciw PA, Shacklett BL: HIV: Molecular Organization, Pathogenicity and Treatment. Morrow WJW, Haigwood NL [editors]. Elsevier, 1993.)
Cells contain intracellular antiviral inhibitory proteins referred to as restriction factors. One type is APOBEC3G, a cytidine deaminase that inhibits HIV replication. The Vif protein promotes viral infectivity by suppressing the effects of APOBEC3G. Another inhibitory protein is TRIM5α, which binds to incoming retrovirus particles and recruits them to proteasomes before much viral DNA synthesis occurs.
The many different isolates of HIV are not identical but appear to comprise a spectrum of related viruses (see Classification). Heterogeneous populations of viral genomes called quasispecies are found in an infected individual. This heterogeneity reflects high rates of viral replication and the high error rate of the viral reverse transcriptase. The regions of greatest divergence among different isolates are localized to the env gene, which codes for the viral envelope proteins (Figure 3). The SU (gp120) product of the env gene contains binding domains responsible for virus attachment to the CD4 molecule and coreceptors, determines lymphocyte and macrophage tropisms, and carries the major antigenic determinants that elicit neutralizing anti bodies. The HIV glycoprotein has five variable (V) regions that diverge among isolates, with the V3 region important in neutralization. The TM (gp41) env product contains both a transmembrane domain that anchors the glycoprotein in the viral envelope and a fusion domain that facilitates viral penetration into target cells. The divergence in the envelope of HIV complicates efforts to develop an effective vaccine for AIDS.
Fig3. HIV-1 envelope proteins. The gp160 precursor polypeptide is shown at the top. The gp120 subunit is on the outside of the cell, and gp41 is a transmembrane protein. Hypervariable domains in gp120 are designated V1 through V5; the positions of disulfide bonds are shown as connecting lines in the loops. Important regions in the gp41 subunit are the fusion domain at the amino terminal and the transmembrane domain (TM). Amino (NH2 ) and carboxyl (COOH) terminals are labeled for both subunits. (Reproduced from Peterlin BM: Molecular biology of HIV. In Levy JA [editor]. The Viruses. Vol 4: The Retroviridae. Plenum, 1995. Modified there from Myers G, et al: Human Retroviruses and AIDS 1993: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Theoretical Biology and Biophysics Group T-10, Los Alamos National Library, Los Alamos, New Mexico.)
Lentiviruses are completely exogenous viruses; in contrast to the transforming retroviruses, the lentiviral genome does not contain any conserved cellular genes. Individuals become infected by the introduction of virus from outside sources.
