Role of CD4 in normal immunity and HIV infection

In this report we have attempted to review our knowledge of the role(s) of CD4 in human T-cell function and the consequences of interactions between CD4 molecules and the human immunodeficiency virus (HIV). The observation in 1981 that antibodies to certain epitopes of CD4 inhibited the immune functions of CD4+ T cells led to the initial suggestion that CD4 molecules play a direct role in T-cell function. Although the precise functions of CD4 remain incompletely understood, a preponderance of evidence suggests that this molecule may in fact serve several critical roles. At least one such role is that of interacting directly with MHC class II molecules on antigen-presenting cells, presumably facilitating cell-to-cell interactions. On activated CD4+ T cells, CD4 molecules can also interact directly with the T-cell receptor complex to influence the immune response. Unfortunately, in addition to interacting with the T-cell receptor and class II MHC determinants, CD4 serves as a high affinity receptor for HIV, the causative agent of AIDS. Not only does interaction between the virus and CD4 initiate viral fusion to the cell membrane and HIV entry but, in addition, a similar molecular interaction initiates fusion between HIV-infected and uninfected CD4+ cells, resulting in the formation of multinucleated syncytia. Since uninfected CD4+ cells are, in effect, recruited into such syncytia, this mechanism may account in part for the depletion of CD4+ T cells in HIV-infected patients. Soluble forms of CD4 produced either by genetic engineering or solid phase peptide synthesis can completely block HIV infectivity and syncytia formation in vitro, remarkably without apparent effects on T-cell immunity. Such molecules are currently being explored for their possible therapeutic effects on HIV infection in vivo.