The virus can be transmitted as free infectious particles or via infected cells for which the virus has tropism (for example, CD4 T cells and macrophages). Infected cells are found in blood, but can also be present in semen or vaginal secretions, as well as breast milk; free virus is present in blood, semen, vaginal fluid, or mother’s milk. As we discuss in the next section, HIV virions can differentially express gp120 variants that bind either CCR5 or CXCR4, thereby influencing the cell types infected. In the genital and gastrointestinal mucosae, which are the dominant sites of primary infection by sexual transmission, HIV virions establish infection initially in a small number of mucosal immune cells that express CCR5—effector memory CD4 T cells, dendritic cells, and macrophages. The virus replicates locally in these cells before spreading via T cells or dendritic cells (mucosal macrophages are nonmigratory) to lymph nodes draining the mucosa. The lymphoid compartment of mucosal tissues is enriched for TH1 and TH17 cells, which express CCR5 (naive T cells and TH2 cells do not), so initial viral replication is favored in these subsets of CD4 T cells. After accelerated replication in regional lymph nodes, where there is a high concentration of CD4 T cells, the virus disseminates widely via the bloodstream, and gains broader access to the gutassociated lymphoid tissues (GALT), where the highest number of CD4 T cells in the body reside.
13-29 HIV variants with tropism for different co-receptors play different roles in transmission and progression of disease.
To establish infection in a new host, HIV must make contact with a CD4expressing immune cell. The cell type targeted is determined by the affinity of viral gp120 for the different chemokine coreceptors: CCR5 or CXCR4. Accordingly, the two major tropism variants of HIV are referred to as ‘R5’ and ‘X4,’ respectively. Because CCR5 dominates on CD4expressing immune cells resident at the major sites of viral transmission—sites that are constantly exposed to commensal microbes and thus harbor large numbers of activated immune cells (mucosal tissues of the female and male genital tracts or rectum for sexual transmission; upper gastrointestinal tract for mothertochild transmission)—CCR5tropic R5 strains of virus are typically required for transmission, and dominate early in infection.
Before HIV can contact CD4expressing immune cells in the genital and intestinal mucosae, it must traverse the epithelium of these tissues. Here, the CCR5tropic variants of the virus also have an advantage. Infection occurs across two types of epithelium: the stratified, or multilayered, squamous epithelium that lines the mucosae of the vagina, foreskin of the penis, ectocervix, rectum, oropharynx, and esophagus; or the singlelayered columnar epithelium lining endocervix, rectum, and upper GI tract. Epithelial cells of the rectum and endocervix can express CCR5 and have been shown to selectively translocate R5, but not X4, HIV variants through the epithelial monolayer. Other molecules expressed by epithelial cells also participate; gp120binding glycosphingolipids expressed by epithelial cells of the vaginal or ectocervical mucosae also foster transcytosis of virus across the epithelium. The rate at which virus can transit epithelial barriers to establish infection is fast. SIV virus has been shown to penetrate the cervicovaginal epithelium within 30 to 60 minutes of exposure.