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Impact of Reproductive Aging On HIV Persistence and Inflammation

生殖衰老对艾滋病毒持续性和炎症的影响

基本信息

批准号：
10433074
负责人：
Sara Gianella Weibel
金额：
$ 84.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2023-09-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433074
关键词：
Affect Age Aging Antigens Bioinformatics Biological Assay Biometry CD4 Positive T Lymphocytes Categories Cells Characteristics Clonality Cohort Studies DNA Data Detection Elongation Factor Environment Enzyme-Linked Immunosorbent Assay Estradiol Estrogens Flow Cytometry Funding Future Genes Genetic Transcription Goals Gonadal Steroid Hormones HIV HIV Infections Hormones IL7 gene Immune Immune response Immunologics Immunology Individual Infection Inflammation Intervention Knowledge Link Maintenance Measures Mediating Menopause National Institute of Allergy and Infectious Disease Natural History Participant Pathogenesis Peptide Initiation Factors Peptides Peripheral Plasma Postmenopause Premenopause Progesterone RNA Recording of previous events Research Role Sampling Scientist Signal Transduction Statistical Models T cell clonality T-Cell Activation T-Lymphocyte Testing Time Transcript Transcription Initiation Transcriptional Activation Transcriptional Regulation United States National Institutes of Health Woman Women&apos s Interagency HIV Study Work antiretroviral therapy base cohort design differential expression exhaustion follow-up hormone therapy immune activation immune function immunological intervention integration site jun Oncogene male men middle age monocyte programs prospective reproductive reproductive senescence senescence sex single-cell RNA sequencing transcription factor transcriptomics virology young woman

项目摘要

ABSTRACT Background. Sex-based differences, largely controlled by sex hormones, affect the natural and treated history of HIV infection and HIV-specific immune responses. Our previous work has shown that estrogen potently represses HIV transcription, thus decreasing cellular HIV RNA in women compared to men. Women also have more robust HIV-specific immune responses than men, but men show more peripheral T-cell activation and proliferation. Unexpectedly, our preliminary data has shown that women undergoing reproductive aging have a progressive increase in levels of inducible cellular HIV RNA transcription, whereas men show a progressive decline in the HIV reservoir as they age. However, our preliminary data lack the power to directly correlate expansion of the reservoir with estrogen levels and we have not identified the underlying mechanisms linking estrogen to HIV persistence. Given the increasing number of women aging with HIV, it is critical to more precisely determine the interplay of HIV persistence and declining sex hormones to design effective HIV cure strategies. Our goal. For aims 1, we will characterize extensively the HIV reservoir and generate immunological data at each time-point for 50 midlife women with HIV (none taking hormone therapy) on antiretroviral therapy (ART) with suppressed HIV RNA and already identified as part of Women's Interagency HIV Study (WIHS) and MACS/WIHS Combined Cohort Study (MWCCS). We will use these data to determine the effect of sex hormones on the HIV reservoir size, transcriptional activity and inflammation over 10 years of follow-up while on ART. For aim 2 and 3, we will use prospectively collected cells from pre- and post-menopausal women to perform detailed mechanistic studies and to evaluate whether the observed increase in the inducible HIV reservoirs is due to changes in transcriptional activation profiles or HIV reservoir dynamics (IL-7 driven homeostatic proliferation and antigen mediated proliferation) during reproductive aging. How will we advance the field? To date, the majority of HIV cure research has used male participants and therefore a significant knowledge gap exists between men and women. We do not know if the same immune- modulatory interventions will be effective in promoting HIV RNA transcription in men and women and how declining sex hormones will impact their efficacy. In particular, agents that are designed for “kick and kill” strategies may be especially impacted by estradiol-mediated mechanisms. A better understanding of these differences will assist in the design of future cure approaches that can be applied across sexes.

摘要