No abstract

The size of the pool of resting CD4+ T cells containing replication-competent HIV in the blood of patients receiving intermittent interleukin (IL)-2 plus highly active anti-retroviral therapy (HAART) was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4+ T cells in three patients receiving IL-2 plus HAART, despite the fact that large numbers of resting CD4+ T cells were cultured. Lymph node biopsies were done in two of these three patients and virus could not be isolated. These results indicate that the intermittent administration of IL-2 with continuous HAART may lead to a substantial reduction in the pool of resting CD4+ T cells that contain replication-competent HIV.

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 HIVspecific memory CD4 ؉ T cells is only rarely demonstrable in HIVinfected 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-␥ 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-␥ 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.