Evaluating the relationship of CD101 and UBE2V1 to genital mucosal inflammation

评估CD101和UBE2V1与生殖器粘膜炎症的关系

基本信息

批准号：
9405665
负责人：
Jairam Rao Lingappa
金额：
$ 70.14万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-14 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9405665
关键词：
5&apos Untranslated Regions AIDS prevention Adherence African Anti-Retroviral Agents Antigens Bacterial Vaginosis Biological Biopsy CCL7 gene CXCL9 gene Cells Couples Data Detection Drug Targeting Drug resistance Effector Cell Enrollment Female Functional disorder Future Gene Frequency Genes Genetic Determinism Genetic Transcription Genital system Genomics HIV-1 Heterosexuals Host resistance Human Herpesvirus 2 Immune Immune response Immunosuppression In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Interleukin-7 Intervention Link Minor Modeling Molecular Mucositis Mucous Membrane Pathway interactions Pattern Pharmaceutical Preparations Plasma Prevention Preventive Intervention Public Health Recruitment Activity Regulation Regulatory T-Lymphocyte Reporting Risk Risk Factors Role Sampling Sexually Transmitted Diseases TNF gene Testing Tissues Untranslated Regions Vaccines Variant Viral Visit Woman chemokine co-infection cost cytokine epidemiology study experience female sex worker genetic association genetic variant genital herpes genital infection genome sequencing hazard immune activation inflammatory milieu men novel novel strategies pathogen pre-exposure prophylaxis prevent reproductive tract risk minimization whole genome

项目摘要

ABSTRACT Global HIV-1/AIDS prevention efforts have been greatly facilitated by the demonstration that anti-retroviral drugs (ARVs) for pre-exposure prophylaxis (PrEP) and treatment as prevention can be effective in preventing the spread of HIV-1. However, the challenges of achieving high adherence, the cost of implementation, and potential for future changes in ARV drug resistance patterns underscore the continuing need for new approaches to HIV- 1 prevention. In particular, novel interventions that target host immune responses may be less likely to elicit viral escape, and may enhance host responses to future HIV-1 prevention vaccines. Genital tract inflammation is known to be associated with altered risk of HIV-1 acquisition. Studies have reported that inflammatory responses to sexually transmitted infections (STI), the presence of genital tract inflammatory cytokines (e.g., IL-7, TNF-α, and IL12p70), chemokines (e.g., CCL7, and CXCL9), and cellular immune activation are associated with increased risk of HIV-1 infection. One explanation for these observations is that these inflammatory environments result in the accumulation of activated immune effector cells, which increase available targets for HIV-1 infection. However, studies of Kenyan female sex workers have found that natural host resistance to HIV-1 infection is associated with lower levels of immune activation (e.g., “immune quiescence”). This reduced immune activation did not reflect a state of broad immunosuppression insofar as these women had otherwise normal host responses to exogenous antigens. This suggests that intrinsic host pathways may regulate genital tract inflammatory responses, and these regulatory mechanisms may alter the risk of HIV-1 infection. However, studies also report that, in some settings, immune activation may be associated with reduced HIV-1 acquisition, raising the caution that use of interventions to broadly induce nonspecific immunosuppression could have unintended effects, such as eliminating effective barriers to HIV-1 or to defenses against other co-infections. The public health challenge is to identify genital tract inflammatory pathway(s) that can mitigate risk of HIV-1 acquisition without increasing risk of other infections. We recently documented the presence of variants in two genes, CD101 and UBE2V1, which are strongly associated with altered HIV-1 infection risk. Both of these genes have been previously reported to have roles in regulating host inflammatory responses. Given these genetic associations with HIV-1 acquisition risk, and a priori evidence that these genes may modify host inflammatory responses, we hypothesize that these genes may modulate HIV-1 acquisition risk through altering underlying host inflammatory responses in the genital tract. Here we propose molecular and epidemiologic studies to evaluate the association of these gene variants with inflammation of the female genital tract.

抽象的抗逆转录病毒药物的应用极大促进了全球 HIV-1/艾滋病预防工作（ARV）用于暴露前预防（PrEP）和预防治疗可以有效预防然而，实现高依从性的挑战、实施成本和潜力抗逆转录病毒药物耐药性模式的未来变化强调了对艾滋病毒新方法的持续需求 1 特别是，针对宿主免疫反应的新型干预措施可能不太可能引发病毒。逃脱，并可能增强宿主对未来 HIV-1 预防疫苗的反应。研究表明，生殖道炎症与 HIV-1 感染风险改变有关。据报道，性传播感染（STI）的炎症反应，生殖道的存在炎症细胞因子（例如 IL-7、TNF-α 和 IL12p70）、趋化因子（例如 CCL7 和 CXCL9）和细胞因子对这些观察结果的一种解释是，免疫激活与 HIV-1 感染风险增加有关。是这些炎症环境导致激活的免疫效应细胞的积累，这增加 HIV-1 感染的可用目标然而，对肯尼亚女性性工作者的研究发现宿主对 HIV-1 感染的天然抵抗力与较低水平的免疫激活有关（例如，“免疫这种免疫激活的减少并不反映广泛的免疫抑制状态。这些女性对外源抗原有正常的宿主反应，这表明内在宿主。途径可能调节生殖道炎症反应，这些调节机制可能然而，研究还报告说，在某些情况下，免疫激活可能会改变。与减少 HIV-1 获得相关，因此需要谨慎使用干预措施来广泛诱导非特异性免疫抑制可能会产生意想不到的影响，例如消除 HIV-1 的有效屏障或防御其他合并感染的公共卫生挑战是确定生殖道。炎症途径可以降低 HIV-1 感染风险而不增加其他感染风险感染。我们最近记录了两个基因 CD101 和 UBE2V1 中存在变异，这些变异与先前已报道这两个基因与 HIV-1 感染风险改变相关。考虑到这些与 HIV-1 感染风险的遗传关联以及先验。有证据表明这些基因可能会改变宿主的炎症反应，我们追求这些基因可能通过改变生殖道中潜在的宿主炎症反应来调节 HIV-1 感染风险。我们提出分子和流行病学研究来评估这些基因变异与女性生殖道炎症。