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

项目摘要/摘要 了解艾滋病毒感染和传播的机制对于新的预防至关重要。 战略。对HIV-1获得和病毒扩展的早期事件的理解仍然存在 不完整的，尤指男性。性传播感染(STI)的发病率会增加HIV-1 收购风险，对收购机制的认识也存在差距。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 被丢弃的包皮以表征男性生殖器组织驻留的HIV-1靶细胞。奇戈林博-齐克瓦医生 将描述HIV-1、淋巴系和髓系靶细胞之间的分子和功能相互作用 从财政司司长那里。这项拟议的研究的一个独特之处在于询问体内激活事件是如何从 细菌性传播感染可以调节体外HIV-1靶细胞的敏感性。我们假设包皮组织 包含几种易受HIV-1感染的细胞系，这些细胞系可以支持病毒扩张和 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将研究淋巴系和髓系细胞之间的表型和转录图谱 从患有和没有无症状细菌性传播感染的男性包皮组织中分离出。目标2，意志 确定免疫激活对淋巴和髓系细胞对HIV-1易感性的影响 感染。Chigorimbo-Tsikiwa博士将用一组HIV-1分离株挑战包皮来源的细胞 评估特定细胞对HIV-1感染的相对易感性。我们将探讨In的影响 通过对STI阳性个体分离的细胞进行HIV-1攻击来激活体内免疫 至于衣原体抗原、内毒素和TLR激动剂对病毒感染性和扩张性的体外激活作用。 干扰素刺激基因(ISG)拮抗剂已被证明在细胞和 对抗其他逆转录病毒。因此，目标3将评估双芳基环烷酮的再利用情况为 ISG激动剂，在各种细胞模型中用作抗HIV-1分子。本研究从人的角度出发进行研究 包皮将为艾滋病毒在男性生殖道的感染和传播提供新的见解 增加该领域的知识，以促进Chigorimbo博士的研究事业发展- 齐克瓦。Chigorimbo-Tsikiwa博士将得到多产出版商首席研究人员的指导， 在传染病生物医学研究方面拥有多项研究奖学金，曾指导 他们在康奈尔大学的David Russell博士和Frank Kirchhoff博士之间大约有40名博士后 德国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，她可以在三大洲进行高科技驱动的研究 在这个K奖的春季寄宿她作为一名独立的非洲艾滋病毒生物医学科学家。

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.