How the HIV-CD4 Interaction Informs Vaccine Development

Soon after HIV-1 was shown to cause AIDS, its primary receptor was identified as CD4, a transmembrane protein on the surface of T-helper lymphocytes, macrophages and dendritic cells. Subsequent studies showed how CD4 binding induces the HIV-1 envelope glycoprotein (Env) to interact with a co-receptor, usually CCR5, and thereby triggers fusion of the viral and cellular membranes, allowing entry of the viral core into the cytoplasm. Antibodies to Env that neutralize viral infectivity (NAbs) by blocking entry are present in sera from HIV-1-positive people. Some NAbs target epitopes overlapping the CD4-binding site (CD4bs) on Env. Most of the initially identified NAbs, including those to the CD4bs, are, however, inactive against circulating HIV-1 strains. Later, monoclonal NAbs with broader activity (bNAbs) were isolated, including a prominent group specific for epitopes overlapping the CD4bs. To induce such potentially protective bNAbs through vaccination has proven challenging. That difficulty is partly explained by the unusual degree of somatic hypermutation in most bNAbs and the inability of their germline B-cell receptors to bind native Env. Env-based immunogens are now engineered to initiate bNAb ontogeny and to steer the antibody response towards neutralization breadth. The CD4bs is a major focus of these germline-targeting strategies.