We propose a multidisciplinary program comprised of four interactive research projects and three supporting cores that thematically seeks to explore biological aspects of HIV infection and pathogenesis that are unique to women. Project I, led by Warner Greene, will study the molecular and cellular basis for HIV infection in the female genital tract using a cervical-vaginal organ culture model coupled with the use of fluorescently labeled virions to monitor the cellular targets and evolution of infection within this mucosal tissue. This project will also investigate the potential function of HIV Vpr as a transcriptional coactivator of the estrogen and progesterone nuclear hormone receptors and study the biological consequences of such a virus-host transcription factor interplay on HIV gene expression. Project II, led by Robert Grant, will explore whether the viral quasi-species present in the female genital tract of HIV infected women differs from that simultaneously circulating in the blood both prior to and after the administration of potent antiviral therapy. Other studies will assess potential defects in the ability of protease inhibitor resistant viruses to infect macrophages and dendritic cells. Project III, led by Marc  Hellerstein, will examine the influence of sex hormones on T-helper cell turnover measured by a combination of flow based cell isolation and mass spectroscopy following deuterated glucose or 2H20 labeling in vivo. These studies will involve the analysis of hypogonadal women and men, postmenopausal women before and after estrogen replacement therapy, and children before and after puberty. Project IV, led by Leslie Benet, will determine the effect of hormonal changes occurring within the ovulatory cycle, during menopause, and after estrogen replacement on P-glycoprotein exporter and cytochrome p450 A enzyme expression and functional activity. Changes in these two proteins will be monitored in the intestine, endometrium and PBMCs. This project will also assess how changes in these proteins may affect the response to HIV protease inhibitors that are all substrates for both proteins. Core A, led by Ruth Greenblatt. will provide clinical coordination of these projects, including recruitment, study visits, participant tracking and compensation. Core B, led by Robert Taylor, will provide reproductive endocrinology consultation, gonadal function assessments and ovulatory cycle staging, and tissue collection. Core C led by Warner Greene will provide overall scientific leadership, data entry and biostatistical analysis for all projects, and administrative support coupled with fiscally sound budget management. Together, these projects and cores combine to form a program that promises to yield new insights into the unique features that underlie gender specific differences in HIV infection and pathogenesis.