To investigate the association of antigen specific CD4 T cell activation with HIV disease progression and AIDS-related central nervous system damage, T cell proliferation responses to HIV, CMV, and HSV were evaluated in infected individuals. CD4 T cell loss and neurocognitive impairment were assessed at 6-mo intervals. Individuals with known times of seroconversion who responded to more HIV peptides were at greater risk of progressing to < 200 CD4 T cells (P = 0.04) and dying (P = 0.03) than those with responses to fewer peptides. A positive correlation (0.52) was seen between the breadth of the HIV proliferation response and HIV plasma RNA levels. Higher proliferation responses to CMV and HSV were also associated with more rapid CD4 loss (P = 0.05). HLA phenotyped individuals (n = 150) with two HLA-DR alleles associated with response to more HIV peptides and CMV (DR-2,5,w6,10) were less likely to develop neurocognitive (P = 0.002) and neurologic impairment (P = 0.04), but were not protected from CD4 loss and death. Thus, the ability to generate a greater T cell proliferation response to HIV and opportunistic herpes viruses may lead to resistance to central nervous system damage, but also risk of more rapid HIV disease progression.