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-l) 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-l 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-l infection (CD4 counts 500-750 cells/uL; n~l5 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 chances 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 affecting 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 I 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.
| Chan, Jonathan K; Bhattacharyya, Darshana; Lassen, Kara G et al. (2013) Calcium/calcineurin synergizes with prostratin to promote NF-?B dependent activation of latent HIV. PLoS One 8:e77749 |
| Chan, Jonathan K L; Greene, Warner C (2011) NF-ýýB/Rel: agonist and antagonist roles in HIV-1 latency. Curr Opin HIV AIDS 6:12-8 |
| Ghotb, Alireza; Noworolski, Susan M; Madden, Erin et al. (2010) Adipose tissue and metabolic factors associated with steatosis in HIV/HCV coinfection: histology versus magnetic resonance spectroscopy. J Acquir Immune Defic Syndr 55:228-31 |
| Roan, Nadia R; Sowinski, Stefanie; Münch, Jan et al. (2010) Aminoquinoline surfen inhibits the action of SEVI (semen-derived enhancer of viral infection). J Biol Chem 285:1861-9 |
| Noworolski, Susan M; Tien, Phyllis C; Merriman, Raphael et al. (2009) Respiratory motion-corrected proton magnetic resonance spectroscopy of the liver. Magn Reson Imaging 27:570-6 |
| Rahangdale, Lisa; Greenblatt, Ruth M; Perry, Jean et al. (2009) In vivo effects of nonoxynol-9 on endometrial immune cell populations. J Acquir Immune Defic Syndr 52:137-9 |
| Weiss, Gerson; Goldsmith, Laura T; Taylor, Robert N et al. (2009) Inflammation in reproductive disorders. Reprod Sci 16:216-29 |
| Chiu, Ya-Lin; Greene, Warner C (2009) APOBEC3G: an intracellular centurion. Philos Trans R Soc Lond B Biol Sci 364:689-703 |
| Cavrois, Marielle; Neidleman, Jason; Greene, Warner C (2008) The achilles heel of the trojan horse model of HIV-1 trans-infection. PLoS Pathog 4:e1000051 |
| Chiu, Ya-Lin; Greene, Warner C (2008) The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu Rev Immunol 26:317-53 |
Showing the most recent 10 out of 34 publications
