HIV gp120 binds Conformational change Conformational change to T cell CD4 in gp120 promotes in gp41 exposes fusion binding to chemokine peptide, which inserts receptor into T cell membrane ■_11_i

FIGURE 20-6 Mechanism of HIV entry into a cell. In the model depicted, sequential conformational changes in gp120 and gp41 are induced by binding to CD4. These changes promote binding of the virus to the coreceptor (a chemokine receptor) and fusion of the HIV-1 and host cell membranes. The fusion peptide of activated gp41 contains hydrophobic amino acid residues that mediate insertion into the host cell plasma membrane.

Fusion of viral and cell membranes and virus production begins. The multiple infections that AIDS patients acquire thus stimulate HIV production and infection of additional cells.

The Tat protein is required for HIV gene expression and acts by enhancing the production of complete viral mRNA transcripts. Even in the presence of optimal signals to initiate transcription, few if any HIV mRNA molecules are actually synthesized without the action of Tat because transcription of HIV genes by mammalian RNA poly-merase is inefficient and the polymerase complex usually stops before the mRNA is completed. Tat protein binds to the nascent mRNA and increases the "processivity" of RNA polymerase by several hundred-fold, which allows transcription to be completed to produce a functional viral mRNA.

Synthesis of mature, infectious viral particles begins after full-length viral RNA transcripts are produced and the viral genes are expressed as proteins. The mRNAs encoding the various HIV proteins are derived from a single full-genome-length transcript by differential splicing events. HIV gene expression may be divided into an early stage, during which regulatory genes are expressed, and a late stage, during which structural genes are expressed and full-length viral genomes are packaged. The Rev, Tat, and Nef proteins are early gene products encoded by fully spliced mRNAs that are exported from the nucleus and translated into proteins in the cytoplasm soon after infection of a cell. Late genes include env, gag, and pol, which encode the structural components of the virus and are translated from singly spliced or unspliced RNA. The Rev protein initiates the switch from early to late gene expression by promoting the export of these incompletely spliced late gene RNAs out of the nucleus. The pol gene product is a precursor protein that is sequentially cleaved to form reverse transcriptase, protease, ribonuclease, and integrase enzymes. As mentioned before, reverse transcriptase and integrase proteins are required to produce a DNA copy of the viral RNA genome and to integrate it as a provirus into the host genome. The gag gene encodes a 55-kD protein that is proteolytically cleaved into p24, p17, and p15 polypep-tides by the action of the viral protease encoded by the pol gene. These polypeptides are the core proteins that are required for assembly of infectious viral particles. The primary product of the env gene is a 160-kD glycoprotein (gp160) that is cleaved by cellular proteases within the endoplasmic reticulum into the gp120 and gp41 proteins required for HIV binding to cells, as discussed earlier. Current antiviral drug therapy for HIV disease includes inhibitors of the enzymes reverse transcriptase, protease, and integrase.

After transcription of various viral genes, viral proteins are synthesized in the cytoplasm. Assembly of infectious viral particles then begins by packaging full-length RNA transcripts of the proviral genome within a nucleoprotein complex that includes the gag core proteins and the pol-encoded enzymes required for the next cycle of integration. This nucleoprotein complex then buds from the plasma membrane, capturing Env and host glycoproteins as part of its envelope. The rate of virus production can reach sufficiently high levels to cause cell death, as discussed later.

A host factor that prevents virion release in certain cell types is a protein called tetherin. Tetherin prevents the pinching off of certain viruses including HIV, and its inhibition of the budding process can be antagonized by an HIV protein called Vpu.

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