HIV: GENDER AND SEX HORMONE EFFECTS ON T CELL KINETICS

描述：(申请者提供摘要)性别差异 记录了免疫功能的许多方面，并可能由 主要生殖激素(雄激素、雌激素和黄体酮)。性别 人类免疫缺陷病毒1型自然病史的差异 (艾滋病毒-L)感染也被描述。特别是，一种不同的 HIV-1病毒载量(VL)与疾病进展的关系已被证实 报告的女性与男性相比。性别或性别在体内的影响 生殖激素对T细胞增殖和存活的影响，包括 胸腺T细胞的产生，在HIV-1感染的背景下还没有 然而，直接进行了测试。我们建议的研究目标是： 比较早期男性和女性T细胞周转率的自然历史 HIV-1疾病和性激素对T细胞的影响 周转，包括胸腺生成，在艾滋病毒-L感染。这些研究现在是 由于稳定同位素质量的最新发展，在人类中可能存在 直接测定精制T动力学的光谱技术 活体内的细胞亚群。将进行三项临床研究。学习 #1将比较CD 4和CD 8 T细胞动力学的自然历史 未经治疗、CD_4相合的男性和女性早期感染艾滋病毒-L(CD_4计数 500-750个/u1；每组n~15个)。T细胞动力学将由两个 补充技术([6，6-2H2]葡萄糖掺入和消亡曲线， 表征记忆/效应表型T细胞动力学；长期2H2O 掺入，以表征幼稚表型T细胞的动力学 然后在3-4年的随访中每隔12-18个月进行一次基线治疗。相关性 VL、CD4计数、胸腺质量(CT扫描)、切除环和血液之间的关系 将对男性和女性的测量结果(细胞因子、激素)进行比较。我们的 假设T细胞动力学中的几率将随着CD4计数的增加而变化 男女都有，但女性的VL较低。研究2将比较以下两种方法的效果 感染艾滋病毒-1的青春期前男孩和女孩的青春期(每组8人)。这个 门诊2H2O法将用于T细胞动力学的测定。其他 参数将像研究1中那样相互关联。中心假设是 性激素的增加会抑制两性的胸腺生成。也许吧 对男孩的影响更大。研究3将比较生育的影响 性腺功能低下的HIV-1成年男性和女性的激素替代治疗 感染(每组8例)。测量T细胞动力学的2H2O方法将 被利用。与研究I和研究2中的其他测量一样。假设是 性激素会减少男性和女性的幼稚表型T细胞的产生 女性，可能对男性的影响更大。总括而言，我们建议 在体内直接确定性类固醇是否改变T细胞动力学 (特别是胸腺生成)在感染HIV-1的人。T细胞是否 与男性相比，女性的周转率与CD4计数的相关性比VL更好。

Description: (Abstract Provided by Applicant) 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.