Mechanisms of type I IFN signaling and HIV risk in the female genital tract

I 型 IFN 信号传导机制与女性生殖道 HIV 风险

• 批准号: 10396670
• 负责人: Aida Sivro
• 金额: $ 13.03万
• 依托单位: CENTRE/AIDS PROGRAMME/RES/SOUTH AFRICA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-22 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396670
• 关键词: 2019-nCoV; Address; Antiviral Response; Biometry; COVID-19; Cells; Chronic; Clinical Research; Clinical Trials; Cohort Analysis; Cohort Studies; Down-Regulation; Enrollment; Epidemiology; Female; Female genitalia; Gel; Gene Expression; Generations; Genes; Genetic Transcription; Genital; Genitalia; HIV; HIV Infections; HIV risk; High Risk Woman; Immune; Immune response; Immunology; Impairment; Implant; In Vitro; Infection; Inflammation; Inflammatory; Interferon Type I; Interferons; International; Intuition; Lead; Link; Location; Macaca mulatta; Measures; Mediating; Modeling; Mucous Membrane; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Predisposition; Prevention; Prospective cohort; Research Personnel; Risk; Role; Sampling; Signal Transduction; Site; South Africa; Surface; Systemic infection; Tenofovir; Testing; Therapeutic; Up-Regulation; Viral; Virus; Virus Diseases; Woman; base; cytokine; desensitization; design; immunopathology; in vitro Model; in vivo; multidisciplinary; nonhuman primate; pandemic disease; prevent; programs; prophylactic; reproductive tract; response; single-cell RNA sequencing; subcutaneous; transcriptomics; transmission process; young woman

ABSTRACT Previously, we carried out large-scale analysis of mucosal cytokines and HIV acquisition in high-risk women from KwaZulu-Natal, South Africa, enrolled as part of the CAPRISA 004 TFV 1% gel study (n = 774). Using a prospective cohort design, we validated our previous finding that inflammatory cytokines increase the risk of HIV acquisition. Of the cytokines associated with increased risk, one of the strongest associations was observed for the key type I IFN, IFN2 (p = 10E-6). Women in upper quartile for IFN2 were at 4-fold greater risk of acquiring HIV, compared to women in the lowest quartile (HR 3.9, 95% CI 1.7-9.1). On the surface this seems counter- intuitive, as type I IFN have strong anti-HIV effects both in vitro and when given in vivo as a therapeutic or prophylactic in non-human primate model. To reconcile these observations, we hypothesize that chronic type I IFN upregulation in the female reproductive tract (FRT) leads to dysregulation of IFN signaling, resulting in downregulation of antiviral genes, increase in generalized inflammation and increase in susceptibility of target cells at the site of infection. This hypothesis would provide an explanation as to why a classical anti- viral program that should be protective actually leads to higher rates of HIV acquisition. Utilizing samples from the ongoing CAPRISA 018 tenofovir alafenamide (TAF) sub-dermal implant trial, we will determine whether prolonged IFN2 upregulation in the FRT leads to decreased IFN responsiveness and IFN-stimulated gene (ISG) expression in genital immune cells. Next, we will formally test if the chronic increase in IFN2 expression and ISG downregulation correspond to breakthrough HIV infections in young women enrolled in CAPRISA 018. Finally, we will use an in vitro PBMC model to determine the mechanism by which prolonged IFN upregulation leads to ISG downregulation and subsequent increase in HIV risk.

抽象的 此前，我们对来自以下地区的高危女性的粘膜细胞因子和艾滋病毒感染情况进行了大规模分析： 南非夸祖鲁-纳塔尔省作为 CAPRISA 004 TFV 1% 凝胶研究的一部分入组 (n = 774)。使用 前瞻性队列设计，我们验证了之前的发现，即炎症细胞因子会增加感染艾滋病毒的风险 获得。在与风险增加相关的细胞因子中，观察到最强的关联之一是 关键的 I 型 IFN，IFNα2 (p = 10E-6)。处于 IFNα2 上四分位数的女性感染 IFNα2 的风险高出 4 倍 与处于最低四分位数的女性相比，艾滋病毒感染率（HR 3.9，95% CI 1.7-9.1）。从表面上看，这似乎是相反的 直观上，因为 I 型干扰素在体外和体内作为治疗或治疗药物时都具有很强的抗 HIV 作用 在非人类灵长类动物模型中具有预防作用。为了协调这些观察结果，我们假设慢性类型 I 女性生殖道 (FRT) 中的 IFN 上调导致 IFN 信号传导失调，从而导致 抗病毒基因下调、全身炎症增加和易感性增加 感染部位的靶细胞。这个假设将解释为什么经典的反 本应具有保护性的病毒计划实际上会导致艾滋病毒感染率更高。使用来自的样本 正在进行的 CAPRISA 018 替诺福韦艾拉酚胺 (TAF) 皮下植入试验，我们将确定是否 FRT 中 IFNα2 的长期上调会导致 IFN 反应性和 IFN 刺激基因 (ISG) 降低 在生殖器免疫细胞中表达。接下来，我们将正式测试 IFNα2 表达的慢性增加是否与 ISG 下调与参加 CAPRISA 018 的年轻女性的艾滋病毒感染突破相对应。 最后，我们将使用体外 PBMC 模型来确定延长 IFN 上调的机制 导致 ISG 下调并随后增加 HIV 风险。