Pathogenic Mechanisms In Hiv Disease

Niaid Extramural Activities

Investigators

Linked publications & trials

Abstract

The immune systems of patients with HIV infection are characterized by a decrease in the number of helper/inducer (CD4) T lymphocytes. In an effort to determine whether these decreases were secondary to decreased T cell production or increased T cell destruction, a series of studies were carried out in which rates of T cell turnover were studied using in vivo labeling of DNA. These studies clearly demonstrated that the decreases in CD4 T cells seen in the setting of HIV infection are due to an increase in cell death and not due to a decrease in cell production. High levels of viral replication were associated with higher levels of CD4 and CD8 T cell turnover. T cells were noted to be comprised of at least two compartments based upon rates of turnover. Similar changes in turnover were noted among cells in peripheral blood and cells in lymphoid tissues. The CD4 T cell declines seen in the setting of progressive HIV infection were previously found to be associated with a progressive skewing of the T cell receptor (TCR) repertoire. In an effort to assess the impact of this skewing on antigen-specific immunity, studies were carried out to assess the impact of HIV infection on TB-specific immunity in patients with co-infection. Suprisingly, despite decreases in the overall CD4+ T cell pool, there were expansions of TB-specific CD4+ T cells as indicated by production of gamma-interferon following stimulation with TB antigen. Studies of patients receiving IL-2 as part of clinical trials on another project revealed that IL-2 directly induces increased rates of apoptosis as well as expansions of a novel subset of CD4+ T cells that co-express the alpha chain of the IL-2 receptor (CD25). More detailed analyses of the CD4+ T cells expanded in vivo in the setting of IL-2 therapy demonstrated that despite being predominantly of a naive phenotype, these cells most likely arise from the peripheral expansion of mature T cells rather than from the differentiation of stem cells.