The hallmark of AIDS is a selective depletion of CD4+ helper-inducer lymphocytes. This defect is believed to result largely from the selective tropism of HIV-1 for this population of cells based on the high affinity of the viral gp120 envelope protein for the CD4 molecule (km = 4 × 10 - ° M). CD4 normally serves as a ligand for MHC II (major histocompatibility complex type II) interaction, but in HIV-1 infection it is used as the primary receptor molecule for HIV-1 targeting. This has been shown conclusively by studies demonstrating (1) direct complexing of gp120 and CD4 during viral infection; (2) viral attachment and infection inhibited by anti-CD4 monoclonal antibodies that prevent gp120 binding; (3) the ability of recombinant CD4 to confer susceptibility to HIV-1 infection to transfected human cells that normally do not express CD4 (e.g., HeLa cells).

A variety of cell types other than helper-inducer lymphocytes are known to express CD4 on their surface and are capable of replicating HIV-1.

These include blood monocytes, tissue macrophages, Langerhans cells in skin, and microglial and multinucleated giant cells in the central nervous system (CNS). These cells generally express smaller amounts of CD4 on their cell surface but nonetheless have been shown to represent important reservoirs for HIV-1 in vivo. Infection of such cells, in fact, may play an important role in the pathogenesis of AIDS by sequestering the virus as described for other lentiviruses such as visna. Other cell types, including neurons, glial cells, B lymphocytes, colorectal epithelial cells, and myeloid precursors, which may or may not express small amounts of CD4 or CD4-related mRNA, have occasionally been shown to support HIV-1 replication, but the pathophysiologic significance of such findings in regard to viral pathogenesis in vivo is uncertain.