The role of CD4 in HIV envelope-mediated pathogenesis

There is now compelling evidence that env-CD4 interactions are central to several complex pathogenic mechanisms in HIV-1 infection. In addition to mediating virus attachment to CD4+ cells, the high affinity interaction of env protein with CD4 is also important in initiating both syncytium formation and syncytium-independent cytopathic effects. In addition, shed gp120 can bind to CD4 on noninfected cells and interfere with the function of these cells while at the same time rendering the cells susceptible to destruction by ADCC, by CD4+ CTLs or by programmed cell death induced by cross-linking of CD4 with gp120 and anti-gp120 followed by cellular activation. Although all of these mechanisms have been demonstrated to operate in vitro, it remains unclear how important each mechanism is in vivo. Nevertheless, the central role of env-CD4 interactions in all of these pathogenic mechanisms highlights the importance of developing effective low molecular weight inhibitors of this reaction.