The mechanism behind the selective depletion of CD4+ cells in HIV infections remains undetermined. Although HIV selectively infects CD4+ cells, the relatively few infected cells in vivo cannot account for the extent of CD4+ T cell depletion suggesting indirect or bystander mechanisms. The role of virus replication, Env glycoprotein phenotype and immune activation (IA) in this bystander phenomenon remains controversial. Using samples derived from HIV-infected patients; we demonstrate that while IA in both CD4+ and CD8+ subsets correlates with CD4 decline, apoptosis in CD4+ and not CD8+ cells is associated with disease progression. As HIV-1 Env glycoprotein has been implicated in bystander apoptosis, we cloned full length Envs from plasma of viremic patients and tested their Apoptosis Inducing Potential (AIP). Interestingly, AIP of HIV-1 Env glycoproteins were found to correlate inversely with CD4:CD8 ratios suggesting a role of Env phenotype in disease progression. In vitro mitogenic stimulation of PBMCs resulted in upregulation of IA markers but failed to alter the CD4:CD8 ratio. However, co-culture of normal PBMCs with Env expressing cells resulted in selective CD4 loss that was significantly enhanced by IA. Our study demonstrates that AIP of HIV-1 Env and IA collectively determine CD4 loss in HIV infection.

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