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Sex difference in intestinal immune dysfunction, SHIV infection and reservoir

肠道免疫功能障碍、SHIV感染和储存者的性别差异

基本信息

批准号：
10462764
负责人：
Theresa L Chang
金额：
$ 76.2万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
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：
2021-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462764
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Acute Animal Model Area Blood CD4 Positive T Lymphocytes Cells Chronic Chronic Disease Disease Outcome Disease Progression ESR1 gene Epithelial Estrogens Exhibits Feedback Female Fluorescent in Situ Hybridization Fostering Gender Gene Expression Genes Goals Gut associated lymphoid tissue HIV HIV Infections HIV-1 Health Human Immune Immune System Diseases Immune response ImmunoPET Infection Inflammatory Interferon-alpha Interferons Interruption Intestines Kinetics Knowledge Longitudinal Studies Macaca mulatta Maps Modeling Molecular Mucosal Immune Responses Pathogenesis Pathway interactions Patients Peripheral Persons Production Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role SIV Sex Differences Signal Transduction Site Social Behavior Spatial Distribution T-Cell Depletion Technology Testing Therapeutic Intervention Time Tissues Viral Viral Load result Viral reservoir Virus Virus Diseases Virus Replication Woman Work acute infection antiretroviral therapy base cell type cytokine gastrointestinal high risk immune activation immunoregulation in vivo insight longitudinal analysis macrophage male men personalized therapeutic response sex simian human immunodeficiency virus single molecule social engagement transcriptome transcriptome sequencing viral RNA viral rebound

项目摘要

PROJECT SUMMARY Gastrointestinal malfunctions and immune activation remain significant health issues for people living with HIV/AIDS in the era of anti-retroviral therapy (ART). Immune activation fuels HIV reservoirs that are established early during infection and support virus rebound after ART interruption (ATI). Increasing evidence points toward sex differences in HIV pathogenesis, disease progression, and persistence. Identifying sex-specific immune parameters associated with viral persistence and rebound will be critical to our long term goal of developing personalized therapeutic strategies to reliably halt HIV-associated chronic diseases, and to target HIV reservoirs. In subjects without ART, women have higher levels of immune activation than men and have a higher risk of developing AIDS. Sex differences in immune activation in HIV-infected subjects on ART are less definitive, possibly due to confounding factors, including gender (involving social/behavior factors) differences in seeking treatment. Recent evidence identifying estrogen receptor 1 as a key regulator of HIV latency in CD4+ T cells suggests the involvement of estrogen signaling in sex-based differences in HIV persistence. However, the role of estrogen in HIV persistence in vivo remains unknown, as estrogen induces type I IFNs and other pro- inflammatory cytokines, resulting in immune activation. Research in this area has been lacking a reliable animal model. In that regard, we have developed a rhesus macaque (RM) model that mimics key features of human HIV infection providing promising avenues for pursuing sex-based difference studies. The model, which employs R5 SHIV C109 intrarectal challenge, displays a spectrum of disease outcomes similar to human AIDS. In this model, fast disease progression occurs in females only, and is accompanied by an uncontrolled robust mucosal immune response. All male RMs tested to date exhibit normal (slow/chronic) progression. We hypothesize that kinetics and magnitude of immune dysregulation that drive viral replication, persistence, and rebound exhibit sex-based differences and that estrogen may partially contribute to sex difference in immune responses and viral persistence. We will determine sex-specific immune cellular and molecular determinants relevant to HIV reservoirs and rebound longitudinally. The contribution of estrogen to sex differences in immune regulation and viral persistence will also be examined. The proposed work is significant because it promises to provide new insights into the cross-talk between intestinal immune activation and viral persistence that are differentially regulated in male and female RMs, which will be critical for developing personalized therapeutic strategies to reliably halt HIV-associated chronic disease, and to target HIV reservoirs.

项目总结