A defining characteristic of HIV is its ability to infect and replicate within activated cells of the immune system. Three immune cell types are the primary targets of HIV infection: CD4 T cells, macrophages, and dendritic cells. Of these, CD4 T cells support the great majority of viral replication. HIV’s ability to enter particular cell types, known as its cellular tropism, is determined by the expression of specific receptors for the virus on the surface of those cells. HIV enters cells by means of a complex of two noncovalently associated viral glycoproteins, gp120 and gp41, which form trimers in the viral envelope. The gp120 subunits of trimeric gp120/gp40 complexes bind with high affinity to the cellsurface molecule CD4, which is expressed on CD4 T cells, and to a lesser extent on subsets of dendritic cells and macrophages. Before fusion and entry of the virus, gp120 must also bind a coreceptor on the host cell. The major coreceptors are the chemokine receptors CCR5 and CXCR4. While CCR5 is predominantly expressed on subsets of effector memory CD4 T cells, dendritic cells, and macrophages, CXCR4 is expressed primarily by naive and central memory CD4 T cells. As we will discuss below, the particular chemokine coreceptor bound by a given viral particle is of importance in the transmission of HIV between individuals and its propagation within an infected person. After binding CD4, gp120 undergoes a conformational change that exposes a highaffinity site that is bound by the coreceptor. This, in turn, causes gp41 to unfold and insert a portion of its structure (fusion peptide) into the plasma membrane of the target cell, inducing fusion of the viral envelope with the cell’s plasma membrane. This allows the viral nucleocapsid, composed of the viral genome and associated viral proteins, to enter the hostcell cytoplasm (Fig. 13.30).
Once the virus has entered cells, it replicates similarly to other retroviruses. Reverse transcriptase transcribes the viral RNA into a complementary DNA (cDNA) copy. The viral cDNA, which encodes nine genes (Fig. 13.31), is then integrated into the hostcell genome by viral integrase, which recognizes and partially cleaves repetitive DNA sequences, called long terminal repeats (LTRs), that reside at each end of the viral genome. LTRs are required for the integration of the provirus into the hostcell DNA and contain binding sites for generegulatory proteins that control expression of the viral genes. The integrated cDNA copy is known as the provirus.
Like other retroviruses, the HIV genome is small, with three major genes— gag, pol, and env. The gag gene encodes the structural proteins of the viral nucleocapsid core, pol encodes the enzymes involved in viral replication, and env encodes the viral envelope glycoproteins. The gag and pol mRNAs are translated to give polyproteins—long polypeptide chains that are then cleaved by the viral protease (encoded by pol) into individual functional proteins. Thus, pol alone encodes the virion’s three major enzymes that are required for viral replication: reverse transcriptase, integrase, and viral protease. The product of the env gene, gp160, has to be cleaved by a hostcell protease into gp120 and gp41, which are then assembled as trimers in the viral envelope. HIV has six other, smaller, regulatory genes encoding proteins that affect viral replication and infectivity in various ways. Two of these, Tat and Rev, perform regulatory functions that are essential early in the viral replication cycle. The remaining four—Nef, Vif, Vpr, and Vpu—are essential for efficient virus production in vivo.