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: 10456919
• 负责人: Nyaradzo Tsitsi Chigorimbo-Tsikiwa
• 金额: $ 11.27万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456919
• 关键词: AIDS Vaccines; African; Agonist; Antibodies; Antigens; Antiviral Agents; Biomedical Research; CD4 Positive T Lymphocytes; Cell Lineage; 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-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; 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; Virus; Virus Diseases; antagonist; base; biomedical scientist; career; career development; chemokine; cytokine; desensitization; drug discovery; dysbiosis; healthy volunteer; immune activation; in vivo; inhibitor; insight; macrophage; 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.

项目概要/摘要 了解艾滋病毒感染和传播的机制对于新型预防至关重要 策略。对 HIV-1 获得和病毒扩散的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) 的发病率会增加 HIV-1 收购风险，并且对机制的理解也存在差距。本研究将利用 医疗男性包皮环切术 (MMC) 在南非推出，这有助于收集其他资料 丢弃的包皮来表征男性生殖器组织中驻留的 HIV-1 靶细胞。奇戈林博-齐基瓦博士 将表征HIV-1、淋巴和骨髓靶细胞之间的分子和功能相互作用 来自FS。所提出的研究的独特之处在于询问体内激活事件如何 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 含有多种易受 HIV-1 感染的细胞谱系，可支持病毒扩增和 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。 目标 1 将研究淋巴细胞和骨髓细胞之间的表型和转录组学特征 从患有或不患有无症状细菌性传播感染的男性的包皮组织中分离出来。目标2，将 确定免疫激活对淋巴和骨髓细胞对 HIV-1 易感性的影响 感染。 Chigorimbo-Tsikiwa 博士将用一组 HIV-1 分离物来挑战包皮衍生细胞， 评估特征细胞对 HIV-1 感染的相对易感性。我们将探讨的影响 通过对从 STI 阳性个体分离的细胞进行 HIV-1 攻击来激活体内免疫 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激活。 干扰素刺激基因（ISG）拮抗剂已被证明可以赋予细胞抗病毒状态 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重新利用： ISG 激动剂在各种细胞模型中用作抗 HIV-1 分子。这项研究基于人类 包皮将为男性生殖道中艾滋病毒的感染和传播提供新的见解 增加该领域的知识，这将促进 Chigorimbo 博士的研究职业发展- 齐基瓦。 Chigorimbo-Tsikiwa 博士将接受多产出版商的首席研究人员的指导， 拥有多项传染病生物医学研究资助，并曾指导 其中大约有 40 名博士后，其中包括康奈尔大学的 David Russell 博士和美国的 Frank Kirchhoff 博士。 德国乌尔姆大学和南非克莱夫·格雷博士。这项研究将使 Chigorimbo-Tsikiwa 博士 通过她的导师关系获得三大洲高科技驱动的研究 在此期间，她作为一名独立的非洲艾滋病毒生物医学科学家获​​得了 K 奖春季寄宿。