gag pol env vif vpr tat rev vpu nef
Transcription of viral genome; integration of viral DNA into host cell genome; binding site for host transcription factors Nucleocapsid core and matrix proteins
Reverse transcriptase, protease, integrase, and ribonuclease Viral coat proteins (gp120 and gp41)
Overcomes inhibitory effect of host cell enzyme (APOBEC3G), promotes viral replication
Increases viral replication; promotes HIV infection of macrophages; blocks cell cycle progression
Required for elongation of viral transcripts
Promotes nuclear export of incompletely spliced viral RNAs
Downregulates host cell CD4 expression; enhances release of virus from cells; counteracts host restriction
Downregulates host cell CD4 and class I MHC expression; enhances release of infectious virus factor tetherin
Abbreviations: LTR, long terminal repeat; gag, group-specific antigen; pol, polymerase; env, envelope; vif, viral infectivity factor; vpr, viral protein r; tat, transcriptional activator; rev, regulator of viral gene expression; vpu, viral protein u; nef, negative effector
FIGURE 20-4 HIV-1 genome. The genes along the linear genome are indicated as differently colored blocks. Some genes use some of the same sequences as other genes, as shown by overlapping blocks, but are read differently by host cell RNA polymerase. Similarly shaded blocks separated by lines indicate genes whose coding sequences are separated in the genome and require RNA splicing to produce functional mRNA. (Modified from Greene W. AIDS and the immune system. Copyright 1993 by Scientific American, Inc. All rights reserved.)
Env is a complex composed of a transmembrane gp41 subunit and an external, noncovalently associated gp120 subunit. These subunits are produced by proteolytic cleavage of a gp160 precursor. The Env complex is expressed as a trimeric structure of three gp120/gp41 pairs. This complex mediates a multistep process of fusion of the virion envelope with the membrane of the target cell (Fig. 20-6). The first step of this process is the binding of gp120 subunits to CD4 molecules, which induces a conformational change that promotes secondary gp120 binding to a chemokine coreceptor. Coreceptor binding induces a conformational change in gp41 that exposes a hydrophobic region, called the fusion peptide, which inserts into the cell membrane and enables the viral membrane to fuse with the target cell membrane. After the virus completes its life cycle in the infected cell (described later), free viral particles are released from one infected cell and bind to an uninfected cell, thus propagating the infection. In addition, gp120 and gp41, which are expressed on the plasma membrane of infected cells before virus is released, can mediate cell-cell fusion with an uninfected cell that expresses CD4 and coreceptors, and HIV genomes can then be passed between the fused cells directly.
The most important chemokine receptors that act as coreceptors for HIV are CXCR4 and CCR5. More than seven different chemokine receptors have been shown to serve as coreceptors for HIV entry into cells, and several other proteins belonging to the seven-transmembrane-spanning G protein-coupled receptor family, such as the leukotriene B4 receptor, can also mediate HIV infection of cells. Different isolates of HIV have distinct tropisms for different cell populations that are related to the specificity of gp120 variants for different chemokine receptors. All HIV strains can infect and replicate in freshly isolated human CD4+ T cells that are activated in vitro. In contrast, some strains will infect primary cultures of human macrophages but not continuous T cell lines (macrophage-tropic, or M-tropic, virus), whereas other strains will infect T cell lines but not macrophages (T-tropic virus). Some virus strains also infect both T cell lines and macrophages (dual-tropic virus). Macrophage-tropic virus isolates express a gp120 that binds to CCR5, which is expressed on macrophages (and some memory T cells), whereas T cell-tropic viruses bind to CXCR4, which is expressed on T cell lines. HIV variants are described as X4 for CXCR4 binding, R5 for CCR5 binding, or R5X4 for the ability to bind to both chemokine receptors. In many HIV-infected individuals, there is a change from the production of virus that uses CCR5 and is predominantly macrophage tropic early in the disease to virus that binds to CXCR4 and is T cell line tropic late in the disease. The T-tropic strains tend to be more virulent, presumably because they infect and deplete T cells more than do M-tropic strains. The importance of CCR5 in HIV infection in vivo is supported by the finding that individuals
Virion binding to CD4 and chemokine receptor
Fusion of HIV membrane with cell membrane; entry of viral genome into cytoplasm
New HIV. virion
Integration of provirus into cell genome
prcwims HIV RNA^
Nucleus ^^ transcript
Cytokine activation of cell; transcription of HIV genome; transport of spliced and unspliced RNAs to cytoplasm
FIGURE 20-5 HIV life cycle. The sequential steps in the life cycle of HIV are shown, from initial infection of a host cell to viral replication and release of a new virion. For the sake of clarity, the production and release of only one new virion are shown. An infected cell actually produces many virions, each capable of infecting cells, thereby amplifying the infectious cycle.
who do not express this receptor on the cell surface because of an inherited homozygous 32-bp deletion in the CCR5 gene are resistant to HIV infection.
Once an HIV virion enters a cell, the enzymes within the nucleoprotein complex become active and begin the viral reproductive cycle (see Fig. 20-5). The nucleoprotein core of the virus becomes disrupted, the RNA genome of HIV is reverse-transcribed into a double-stranded DNA form by viral reverse transcriptase, and the viral DNA enters the nucleus. The viral integrase also enters the nucleus and catalyzes the integration of viral DNA into the host cell genome. The integrated HIV DNA is called the provirus. The provirus may remain transcriptionally inactive for months or years, with little or no production of new viral proteins or virions, and in this way HIV infection of an individual cell can be latent.
Transcription of the genes of the integrated DNA provirus is regulated by the LTR upstream of the viral structural genes, and cytokines or other physiologic stimuli that trigger T cells and macrophages enhance viral gene transcription. The LTRs contain polyadenylation signal sequences, the TATA box promoter sequence, and binding sites for two host cell transcription factors, NF-kB and SP1. Initiation of HIV gene transcription in T cells is linked to activation of the T cells by antigen or cytokines. For example, polyclonal activators of T cells, such as phytohemagglutinin, and cytokines such as IL-2, tumor necrosis factor (TNF), and lymphotoxin stimulate HIV gene expression in infected T cells, and IL-1, IL-3, IL-6, TNF, lymphotoxin, IFN-y, and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate HIV gene expression and viral replication in infected monocytes and macrophages. TCR and cytokine stimulation of HIV gene transcription probably involves the activation of NF-kB and its binding to sequences in the LTR. This phenomenon is significant to the pathogenesis of AIDS because the normal response of a latently infected T cell to a microbe may be the way in which latency is ended
1 HIV virion
1 HIV virion
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