Biography

Both aging and HIV disease are characterized by the loss of immune control over viral infections and by increased cancer incidence. Our approach to dissecting the complex T cell dysfunction associated with these clinical problems has been to focus on a particular facet of T cell biology known as replicative senescence. This irreversible state of cell cycle arrest, which occurs after T cells have undergone multiple rounds of antigen-driven proliferation, is associated with various functional and genetic changes, such as loss of expression of a key co-stimulatory molecule, CD28), resistance to apoptosis, telomere shortening, and loss of the ability to upregulate telomerase. We have documented that the proportions of T cells with these same characteristics increase with age and with HIV disease progression. Ongoing studies in the lab are addressing the functional aspects of senescent T cells that may contribute to multiple pathologies of aging and AIDS, such as their effect on anti-viral effector activities, alterations in cytokine profiles, and suppressive influences on other types of immune cells. In addition, based on clinical correlations between chronic T cell activation and bone loss, we are interested in the interaction of senescent T cells with osteoclasts and osteoblasts, the cells responsible for bone homeostasis. Finally, we are attempting to reverse or retard the process of replicative senescence in human T cells using telomerase gene therapy, manipulation of CD28 expression, and chemical/hormonal treatment to enhance telomerase activity.

Rita Effros's Abstract