CD4 is a molecule that is found on a subset of T-lymphocytes called T-helper cells and other cells involved in immune function including macrophages. During antigen presentation, the CD4 molecule on T-helper cells binds to a nonpolymorphic region of MHC Class ll. This interaction of CD4 with MHC ll is involved in the initial stages of signal transduction leading to T-cell activation.
CCR5 is a receptor for pro-inflammatory chemotactic cytokines (chemokines), RANTES, MIP-1 alpha, and MIP-1 bata. The latter two chemokines are secreted by macrophages, neutrophils and endothelial cells; RANTES is secreted by T-cells and platelets. These cytokines are chemotactic, up-regulate the expression of a number of adhesion molecules and their ligands, increase binding affinity of these molecules, and generally exert their influence by recruiting cells to the site of antigen exposure through cellular extravasation. CXCR4 (Fusin) is also a chemokine receptor. Its' natural ligand has been identified as SDF-1.
In vivo, HIV-1 seems to have developed a cellular tropism that is determined by the amino acid sequence within the V3 region of the env gene. There seems to be at least two genetic types: HIV-1 strains that will infect primary T-cells and macrophages (Macrophage tropic strains), and HIV-1 strains that will infect primary T-cells but not macrophages ( T-cell tropic strains). The latter strains can, as well, infect T-cell lines while the former strains cannot. CXCR4 is expressed on naive (nonactivated) T-cells. CCR5 is expressed on activated/memory T-cells and macrophages.
Transmission of HIV-1 through sexual activity is thought to occur by the virus that uses CD4 and CCR5 for entry into a cell, probably a macrophage, although the absolute requirement for CCR5 has not been firmly established for primary HIV-1 macrophage tropic isolates. Also, since there seems to be a progressive loss of T-cells of the memory phenotype with disease progression, it is not clear why a T-cell tropic virus with the requirement of CD4 and CXCR4 should be the predominant virus at this stage of infection.
Individuals who are homozygous for a gene that causes a defect in the CCR5 receptor are resistant to infection by HIV-1. Individuals that have two normal genes and express functional CCR5 receptors vary widely in the cell membrane expression of this molecule. The reason for this variability is not known. Also, a SDF-1 genetic polymorphism, when homozygous, seem to delay the onset of HIV pathogenesis.