In chronic viral infections of humans and experimental animals, virus-specific CD4⁺ T cell function is believed to be critical for induction and maintenance of host immunity that mediates effective restriction of viral replication. Because in vitro proliferation of HIV-specific memory CD4⁺ T cells is only rarely demonstrable in HIV-infected individuals, it is presumed that HIV-specific CD4⁺ T cells are killed upon encountering the virus, and maintenance of CD4⁺ T cell responses in some patients causes the restriction of virus replication. In this study, proliferative responses were absent in patients with poorly restricted virus replication although HIV-specific CD4⁺ T cells capable of producing IFN-γ were detected. In a separate cohort, interruption of antiretroviral therapy resulted in the rapid and complete abrogation of virus-specific proliferation although HIV-1-specific CD4⁺ T cells were present. HIV-specific proliferation returned when therapy was resumed and virus replication was controlled. Further, HIV-specific CD4⁺ T cells of viremic patients could be induced to proliferate in response to HIV antigens when costimulation was provided by anti-CD28 antibody in vitro. Thus, HIV-1-specific CD4⁺ T cells persist but remain poorly responsive (produce IFN-γ but do not proliferate) in viremic patients. Unrestricted virus replication causes diminished proliferation of virus-specific CD4⁺ T cells. Suppression of proliferation of HIV-specific CD4⁺ T cells in the context of high levels of antigen may be a mechanism by which HIV or other persistently replicating viruses limit the precursor frequency of virus-specific CD4⁺ T cells and disrupt the development of effective virus-specific immune responses.