The relationship between human immunodeficiency virus (HIV) type 1 replication and CD4⁺ T cell function was examined. T lymphocyte proliferation in response to both HIV-1 antigens and recall antigens was measured in HIV-1—infected individuals before and after they received highly active antiretroviral therapy (HAART). No correlation was observed between baseline viral load or CD4⁺ T cell count and the T cell proliferative response to HIV-1 Gag. Suppression of viremia was not associated with an increase in T cell proliferative responses. Emergence of viral replication during short periods of intermittent therapy promoted generalized activation of T helper lymphocytes, manifested by increased T cell proliferative responses to HIV-1 Gag and recall antigens. Recovery of CD4⁺ T cell responses occurred in some individuals who initiated HAART years after infection and who were intermittently adherent to drug treatment. Thus, CD4⁺ T cell responses can sometimes be regenerated if viral load is suppressed to allow some immune recovery and if antigenic stimulation is later provided.