THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) CD4 RECEPTOR AND ITS CENTRAL ROLE IN PROMOTION OF HIV-1 INFECTION

Interactions between the viral envelope glycoprotein gp120 and the cel l surface receptor CD4 are responsible for the entry of human immunode ficiency virus type 1 (HIV-1) into host cells in the vast majority of cases. HIV-1 replication is commonly followed by the disappearance or receptor downmodulation of cell surface CD4. This potentially renders cells nonsusceptible to subsequent infection by HIV-1, as well as by o ther viruses that use CD4 as a portal of entry. Disappearance of CD4 f rom the cell surface is mediated by several different viral proteins t hat act at various stages through the course of the viral life cycle, and it occurs in T-cell lines, peripheral blood CD4(+) lymphocytes, an d monocytes of both primary and cell line origin. At the cell surface gp120 itself and in the form of antigen-antibody complexes can trigger cellular pathways leading to CD4 internalization. Intracellularly, th e mechanisms leading to CD4 downmodulation by HIV-1 are multiple and c omplex; these include degradation of CD4 by Vpu, formation of intracel lular complexes between CD4 and the envelope precursor gp160, and inte rnalization by the Nef protein. Each of the above doubtless contribute s to the ultimate depletion of cell surface CD4, although the relative contribution of each mechanism and tire manner in which they interact remain to be definitively established.