Cell-cycle dysregulation in the immunopathogenesis of AIDS

For a number of years the pathogenesis of AIDS was thought to be essentially related to direct human immunodeficiency virus (HIV)-mediated killing of CD4+ T cells. More recently, attention has shifted to pathogenic models that emphasize the role of generalized immune system activation and the excess apoptosis of uninfected T cells in inducing HIV-associated CD4+ T-cell depletion. The main focus of our research is to better define the determinants and the consequences of these "indirect" mechanisms of immunodeficiency by Studying both HIV-infected patients and nonhuman primates infected with simian immunodeficiency virus (SIV). We have discovered that pathogenic models of retroviral infections of primates (i.e., HIV infection in humans and SIV infection in rhesus macaques) are associated with the presence of a set of perturbations of normal cell-cycle control in T lymphocytes. These perturbations, to which we collectively refer to as cell-cycle dysregulation. or CCD, may represent an important biological link between chronic immune activation and excess apoptosis and therefore may play a significant role in the pathogenesis of AIDS. A better understanding of the determinants and consequences of CCD may pave the way for the introduction of new therapeutic strategies to be used in addition to standard antiretroviral therapy in HIV-infected patients.