Lymphocyte-proliferative responses (LPRs) to HIV antigens are absent or of low magnitude in the majority of HIV-infected individuals, even early in the disease. However, lymphocytes from 2% to 3% of individuals proliferate very strongly to HIV Env or Gag antigens, and these individuals remain well clinically, without antiretroviral therapy. In established HIV infection, suppression of HIV-replication with potent antiretroviral therapy does not result in the development of strong LPRs to HIV antigens. Large LPRs to HIV antigens can be induced by HIV vaccines in patients with established infection, even though they were not formed in response to infection. Studies must be designed to determine whether large LPRs induced by vaccines administered in conjunction with potent antiretroviral therapy are associated with long-term control of HIV infection.