Research Project III

Gender and Sex Hormone Effects on T Cell Kinetics in HIV Disease

Principal Investigator:

Marc K. Hellerstein, M.D., Ph.D.

Professor of Nutritional Services, University of California, Berkeley

Professor of Medicine, Division of Endocrinology, University of California, San Francisco

Abstract of Research Plan

Gender differences have been documented for many aspects of immune function and are likely mediated by the major reproductive hormones (androgens, estrogens and progesterone). Gender differences in the natural history of human immunodeficiency virus-type 1 (HIV-1) infection have also been described. In particular, a different relationship between HIV-1 viral load (VL) and progression of disease has been reported for women as compared to men. The in vivo effects of gender or reproductive hormones on proliferation and survival of T cells, including thymic production of T cells, in the setting of HIV-1 infection have not been directly tested, however. The objectives of our proposed studies are to compare the natural history of T cell turnover in men and women with early HIV-1 disease and to establish the consequences of sex steroids on T cell turnover, including thymopoiesis, in HIV-1 infection. These studies are now possible in humans because of the recent development of stable isotope-mass spectrometric techniques for directly measuring the kinetics of purified T cell subpopulations in vivo. Three clinical studies will be performed. Study #1 will compare the natural history of CD4⁺ and CD8⁺ T cell kinetics in untreated, CD4-matched men and women with early HIV-1 infection (CD4 counts 500-750 cells/µL; n=15 per group). T cell kinetics will be measured by two complementary techniques ([6,6-²H₂] glucose incorporation and die-away curves, to characterize memory/effector-phenotype T cell dynamics; long term ²H₂O incorporation, to characterize kinetics of naive-phenotype T cells) at baseline then every 12-18 months over a 3-4 year follow-up. Correlation between VL, CD4 count, thymic mass (by CT scan), excision circles, and blood measurements (cytokines, hormones) will be compared in men and women. Our hypothesis is that changes in T cell kinetics will track with CD4 count in both genders, but at a lower VL in women. Study #2 will compare the effects of puberty in HIV-1 infected pre-adolescent boys and girls (n=8 per group). The outpatient ²H₂O approach will be used to measure T cell dynamics. Other parameters will be correlated as in study #1. The central hypothesis is that the rise in sex steroids will suppress thymopoiesis in both genders, perhaps greater effecting boys. Study #3 will compare the effects of reproductive hormone replacement therapy in hypogonadal adult men and women with HIV-1 infection (n=8 per group). The ²H₂O method for measuring T cell dynamics will be used, with other measurements as in Studies 1 and 2. The hypothesis is that sex steroids will reduce production of naive-phenotype T cells in both men and women, with perhaps a greater effect in men. In summary, we propose to determine directly, in vivo, whether sex steroids alter T cell kinetics (particularly thymopoiesis) in HIV-1 infected humans, and whether T cell turnover tracks better with CD4 count than VL in women, compared to men.