Weiss L, Donkova-Petrini V, Caccavelli L, et al. Blood. 2004;104:3249–3256
Purpose of the Study.
HIV infection is associated with a progressive decline in CD4+ T-cell numbers. However, multiple mechanisms of HIV-associated T-cell dysfunction have been described, including reduced HIV-specific lymphoproliferative and cytotoxic T-cell responses and failure to generate proinflammatory cytokines. A CD4+ T-cell subset with regulatory properties has been characterized. These cells, regulatory T cells (Tregs), express CD25 and inhibit the proliferation of T lymphocytes both in vitro and in vivo. This suppression may be antigen specific and cytokine mediated.
Peripheral blood T cells were obtained from clinically stable, antiretroviral-treated HIV-infected individuals with CD4+ T cells >500/mm3 and plasma HIV RNA <50 copies per mL. These cells were used for extensive flow-cytometric analysis, proliferation and suppression assays, and expression of FOXP3, a transcription factor in Tregs.
HIV-infected individuals had increased numbers of CD4+CD25+ T cells with the phenotypic, molecular, and functional characteristics of Tregs. This expanded population persisted despite long-term viral control. Patient Tregs suppressed CD4+ T-cell proliferation to recall antigens and specific HIV proteins. The proliferative capacity of T cells to recall and p24 antigens significantly increased after the depletion of Tregs. Additionally, these T cells responded specifically to p24 antigen with expression of transforming growth factor β and interleukin 10. It is interesting to note that the suppressive activity by the cell population did not depend on secretion of transforming growth factor β or interleukin 10.
HIV derives expansion of CD4+CD25 regulatory T cells. This regulatory T-cell subset in turn suppresses HIV-specific CD4+ T-cell responses in HIV-infected patients.
HIV induces an immunodeficiency by depleting CD4+ T cells. However, demonstrable immunodeficiency occurs before the onset of severe peripheral T-cell depletion. A variety of mechanisms have been invoked to explain this process. The present study demonstrates an additional potential mechanism by which HIV subverts immune responses to both HIV-specific antigens and to those of other infectious agents. The expansion of HIV-induced Tregs suggests a mechanism by which HIV induces partial tolerance to its own antigens. Therapeutic strategies aimed at reducing HIV-specific Tregs might allow more effective control of HIV replication. Alternatively, species-specific simian immunodeficiency viruses seem to induce little disease caused by immune silence. Perhaps enhancement of HIV-specific Tregs rather than suppression of them might result in similar tolerance and lack of disease progression in HIV-infected humans.