Impact of asymptomatic sexually transmitted infections and interferon agonists on the susceptibility of foreskin primary cells to HIV-1 infection.

无症状性传播感染和干扰素激动剂对包皮原代细胞对 HIV-1 感染易感性的影响。

• 批准号: 10673730
• 负责人: Nyaradzo Tsitsi Chigorimbo-Tsikiwa
• 金额: $ 1.51万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673730
• 关键词: African; Agonist; Antibodies; Antigens; Antiviral Agents; Biomedical Research; CD4 Positive T Lymphocytes; Cell Lineage; Cell Separation; Cell model; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chlamydia; Chlamydia trachomatis; Chronic; Collection; Communicable Diseases; Data; Engineering; Event; Flow Cytometry; Funding; Gene Expression; Genes; Genital; Genitalia; Germany; Grant; HIV; HIV Infections; HIV vaccine; HIV-1; Hepatitis B; Hepatitis C Therapy; Human; Immune; Immune Targeting; Immunobiology; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Interferons; International; Investigation; K-Series Research Career Programs; Knowledge; Label; Langerhans cell; Lead; Length; Lymphoid; Lymphoid Cell; Macrophage; Male Circumcision; Male Genital Organs; Mediating; Medical; Mentors; Mentorship; Modeling; Molecular; Mucous Membrane; Myelogenous; Myeloid Cells; Natural Immunity; Oligonucleotides; Outcomes Research; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Population; Postdoctoral Fellow; Predisposition; Prevention strategy; Probability; Protocols documentation; Publications; Reporter; Research; Research Personnel; Research Project Grants; Retroviridae; Risk; Role; Sexually Transmitted Diseases; Signal Transduction; South Africa; Suspensions; Techniques; Technology; Tissues; Training; Ubiquitin; United States National Institutes of Health; Universities; Viral; Viral Physiology; Virus; Virus Diseases; antagonist; biomedical scientist; career; career development; chemokine; cytokine; desensitization; drug discovery; dysbiosis; healthy volunteer; immune activation; in vivo; inhibitor; insight; male; men; microbial; novel; penis foreskin; programs; recruit; reproductive tract; research study; response; sexual HIV transmission; transcriptomics; transmission process

Project Summary/Abstract Understanding the mechanisms involved in HIV acquisition and transmission is critical for novel prevention strategies. The understanding of early events in HIV-1 acquisition and expansion of the virus remains incomplete, especially in males. The incidence of sexually transmitted infections (STI’s) can increase HIV-1 acquisition risk, and there exist gaps in understanding the mechanisms also. This study will exploit the medical male circumcision (MMC) roll out in South Africa, which facilitates the collection of otherwise discarded foreskins to characterize male genital tissue-resident HIV-1 target cells. Dr Chigorimbo-Tsikiwa will characterize the molecular and functional interactions between HIV-1 , lymphoid and myeloid target cells from the FS. A uniqueness of the proposed study lies in interrogating how in vivo activating events from bacterial STIs can modulate ex vivo HIV-1 target cell susceptibility. We hypothesize that foreskin tissue contains several cell lineages that are susceptible to HIV-1 infection that can support viral expansion and that the increased inflammatory response induced by asymptomatic STIs will exacerbate this susceptibility. Aim 1 will investigate the phenotypic and transcriptomic profiles between lymphoid and myeloid cells isolated from the foreskin tissues from men with and without asymptomatic bacterial STIs. Aim 2, will determine the impact of immune activation on the susceptibility of lymphoid and myeloid cells to HIV-1 infection. Dr Chigorimbo-Tsikiwa will challenge foreskin-derived cells with a panel of HIV-1 isolates to assess the relative susceptibility of characterized cells to HIV-1 infection. We will explore the impact of in vivo immune activation by performing HIV-1 challenge on cells isolated from STI-positive individuals as well as to in vitro activation using Chlamydia antigens, LPS and TLR agonists on viral infectivity and expansion. Interferon stimulated genes, (ISG’s) antagonists have been shown to confer an antiviral state in cells and against other retroviruses. Therefore, aim 3 will assess the repurposing of bis-arylidenecycloalkanones as ISG agonist for use as anti -HIV-1 molecules in various cell models. This research study based from human foreskins will provide novel insights in HIV acquisition and transmission in the male genital tract and increase knowledge in the field which will facilitate the research career development of Dr Chigorimbo- Tsikiwa. Dr Chigorimbo-Tsikiwa will receive mentorship from lead researchers who are prolific publishers, possess several research grants in infectious disease biomedical research who have mentored approximately 40 post-docs between them in Dr David Russell at Cornell University, Dr Frank Kirchhoff at Ulm University in Germany and Dr Clive Gray in South Africa. This study will allow Dr Chigorimbo-Tsikiwa access to high technology driven research in three continents afforded by her mentorship relationships during this K award spring boarding her as an independent African HIV biomedical scientist.

项目总结/摘要 了解艾滋病毒获得和传播的机制对于新的预防至关重要 战略布局对HIV-1感染和病毒扩散早期事件的理解仍然存在 不完整，尤其是男性。性传播感染（STI）的发病率可以增加HIV-1 采购风险，在了解机制方面也存在差距。这项研究将利用 医疗男性包皮环切术（MMC）在南非推出，这有助于收集其他 丢弃的包皮来表征男性生殖器组织驻留的HIV-1靶细胞。Chigorimbo-Tsikiwa博士 将描述HIV-1、淋巴和骨髓靶细胞之间的分子和功能相互作用 从FS。所提出的研究的一个独特之处在于询问体内激活事件是如何从 细菌性STI可以调节离体HIV-1靶细胞的易感性。我们假设包皮组织 含有几种易受HIV-1感染的细胞谱系，可支持病毒扩增， 无症状性传播感染引起的炎症反应增加将加剧这种易感性。 目的1将研究淋巴细胞和髓细胞之间的表型和转录谱 分离自患有和不患有无症状细菌性STI的男性的包皮组织。目标二，威尔 确定免疫激活对淋巴细胞和骨髓细胞对HIV-1易感性的影响 感染Chigorimbo-Tsikiwa博士将用一组HIV-1分离物挑战包皮衍生细胞， 评估表征细胞对HIV-1感染的相对易感性。我们将探讨在 通过对分离自STI阳性个体的细胞进行HIV-1攻击， 关于使用衣原体抗原、LPS和TLR激动剂对病毒感染性和扩增的体外活化。 干扰素刺激基因（ISG）拮抗剂已显示在细胞中赋予抗病毒状态， 对抗其他逆转录病毒因此，目标3将评估双亚芳基环烷酮的再利用， 在各种细胞模型中用作抗HIV-1分子的ISG激动剂。这项研究基于人类 包皮将提供新的见解艾滋病毒的收购和传播的男性生殖道， 增加该领域的知识，这将有助于Chigorimbo博士的研究职业发展- 齐基瓦Chigorimbo-Tsikiwa博士将接受来自多产出版商的主要研究人员的指导， 在传染病生物医学研究方面拥有多项研究赠款， 大约有40名博士后，康奈尔大学的大卫罗素博士， 德国的乌尔姆大学和南非的克莱夫格雷博士。这项研究将使奇戈林博-齐基瓦博士 通过她的导师关系，她可以在三大洲获得高科技驱动的研究 在这个K奖春季寄宿她作为一个独立的非洲艾滋病毒生物医学科学家。