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: 10053750
• 负责人: Nyaradzo Tsitsi Chigorimbo-Tsikiwa
• 金额: $ 10.94万
• 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/10053750
• 关键词: AIDS Vaccines; African; Agonist; Antibodies; Antigens; Antiviral Agents; Biomedical Research; CD4 Positive T Lymphocytes; Cell Lineage; Cell model; Cells; Chlamydia; Chlamydia trachomatis; Chronic; Collection; Communicable Diseases; Data; Engineering; Epitopes; Event; Expression Profiling; Flow Cytometry; Funding; Gene Expression; Genes; Genital system; 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; base; biomedical scientist; career; career development; chemokine; cytokine; desensitization; drug discovery; dysbiosis; healthy volunteer; immune activation; in vivo; indexing; inhibitor/antagonist; insight; macrophage; male; men; microbial; novel; penis foreskin; programs; recruit; reproductive tract; research study; response; sexual HIV transmission; transcriptome; 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.

项目摘要/摘要 了解艾滋病毒获取和传播所涉及的机制对于新型预防至关重要 策略。对HIV-1获取和病毒扩张中早期事件的理解仍然存在 不完整，尤其是在男性中。性传播感染（STI）的事件可以增加HIV-1 获取风险，并且也存在理解机制的差距。这项研究将利用 医疗男性电路（MMC）在南非推出，这促进了否则的收集 丢弃的法人表征男性生殖器组织居住的HIV-1靶细胞。 Chigorimbo-tsikiwa博士 将表征HIV-1，淋巴样和髓样靶细胞之间的分子和功能相互作用 来自FS。拟议研究的独特性在于询问体内如何激活事件 细菌性传播感染可以调节体内HIV-1靶细胞敏感性。我们假设包皮组织 包含几个容易受到HIV-1感染感染的细胞谱系，这些谱系可以支持病毒膨胀和 无症状性传播感染引起的炎症反应增加将使这种敏感性加剧。 AIM 1将研究淋巴样和髓样细胞之间的表型和转录谱 从有或没有无症状细菌性传播症的男性的外皮组织中分离出来。目标2，威尔 确定免疫激活对淋巴样和髓样细胞对HIV-1的敏感性的影响 感染。 Chigorimbo-tsikiwa博士将用一系列HIV-1分离株挑战包皮细胞 评估特征细胞对HIV-1感染的相对敏感性。我们将探讨IN的影响 通过对从STI阳性个体分离的细胞进行HIV-1挑战来激活体内免疫激活 至于使用衣原体抗原，LPS和TLR激动剂在病毒感染和膨胀方面进行体外激活。 干扰素刺激的基因，（ISG）拮抗剂已被证明与细胞中的抗病毒状态有关 针对其他逆转录病毒。因此，AIM 3将评估双甲环烷烃的重新利用为 在各种细胞模型中用作抗-HIV -1分子的ISG激动剂。这项基于人类的研究 前包将在男性生殖道和 增加该领域的知识，这将促进Chigorimbo博士的研究职业发展 - tsikiwa。 Chigorimbo-tsikiwa博士将获得多产出版商的主要研究人员的精神职位， 在传染病生物医学研究中拥有几项研究补助 他们在康奈尔大学的戴维·罗素（David Russell）博士弗兰克·基希霍夫（Frank Kirchhoff） 德国的ULM大学和南非的Clive Gray博士。这项研究将允许Chigorimbo-tsikiwa博士 通过她的Mentalship关系提供的三大洲的高科技驱动研究 在这个K奖中，春季登上了她，成为一名独立的非洲艾滋病毒生物医学科学家。