Dr. Dale Isaak
Department of Molecular Biology
University of Wyoming
Laramie, WY 82071
Infection with HumanImmuno-deficiency Virus-I (HIV-1) results in a profound and selective loss of CD4+ T cells, leading toprogressive immunodeficiency that culminates in Acquired Immunodeficiency Syndrome (AIDS) and associated fatal opportunistic infections. Although more than 15 years have passed since the discovery of HIV-1 and AIDS, we still do not fully understand all the mechanisms involved in CD4+ T cell depletion by HIV-1. Direct HIV-mediated cytopathicity in infected CD4=T cells is an important primary mechanism, but a variety of in vitro and in vivo studies have also implicated indirect mechanisms that result in the death of uninfected bystander cells as well. Notable among these are the studies demonstrating large numbers of uninfected cells experiencing a programmed cell death pathway termed apoptosis.
Apoptosis is a closely regulated pathway of cell suicide that is critical to many physiological processes, including T-cell development and normal immune function. The ability of HIV-1 to induce apoptosis in uninfected bystander CD4+ cells may represent an important mechanism to prevent effective immune elimination of both virus and virus-infected cells, as these cells are of central importance in normal immune system function.
My laboratory is investigating the mechanism(s) by which HIV-1 induces apoptosis and the role of apoptosis in the pathogenesis of AIDS onset. We are particularly interested in studying the variability of different strains in inducing apoptosis and the identification of HIV-1 gene products important in apoptosis induction. Finally, we are attempting to understand the importance of CD4+ T cell activation pathways and their role in establishing susceptibility or resistance to HIV-induced apoptosis. These studies are being pursued in a variety of in vitro infection culture approaches as well as in an in vivo system involving SCID mice reconstituted with human T cells via the implantation of fetal human thymic tissue and human hematopoietic stem cells.
Rapaport, E.R., Casella,C.R., Isaak,D.D., Finkel,T.H. Quantitation of apoptosis and infection in T cells infected with HIV-1 in vitro: Persistent infection correlates with a lack of apoptosis in productively infected T cells. In Preparation.
(1997) Lake, J.P., Kennedy,J.D., Isaak, D.D. Moloney murine leukemia virus pathogenesis in euthymic and thymus-deficient nude mice. Submitted.
(1997) Isaak, D.D. Lake, J.P. T-cell activation by superantigen enhances retrovirus pathogenicity in murine leukemia virus Moloney-infected gnotobiotic mice. Proc. 12th Internatl. Symp. Gnotobiology, in press.
(1994) Hiddinga, J., Isaak, D.D., Lewis, R.V. Enkephalin containing peptides processed from proenkephalin significantly enhance the antibody forming cell responces to antigen. J. Immunol. 152, 3748-3759.