Barrier integrity, microbiome and HIV target cell interactions in the human male genital tract pre and post circumcision

男性通过阴茎感染艾滋病毒是艾滋病毒传播研究最少的方面之一。 医学男性包皮环切术（MMC）已在临床试验中显示，以减少艾滋病毒感染的风险， 异性恋男人目前还不完全清楚MMC如何减少男性异性传播。 一种可能的解释是MMC后阴茎的尿道和皮肤粘膜屏障发生了变化 来加强对艾滋病病毒的防御。另一种可能性是包皮本身特别 易受艾滋病毒感染，防御能力较弱，使病毒更容易到达易感免疫者 靶细胞当一个未割包皮的男人患有性传播疾病时， (STI)会产生局部免疫反应和募集易感的HIV靶细胞。这些 本研究的基础是确定阴茎粘膜屏障的变化 MMC之后我们将招募几组18-35岁的性活跃男性， MMC在芝加哥和开普敦，并从性病诊所在开普敦。为了解决潜在的作用， 性传播感染，我们还将在开普敦招募衣原体无症状阳性的男性 沙眼衣原体（CT）或人乳头瘤病毒（HPV）。为监察本地环境的转变，我们会 在CT治疗或MMC治疗后随访2-6个月。我们会测量阴茎的变化 使用体内监测跨上皮水分损失（TEWL）的皮肤完整性，并收集包皮用于 基于实验室的调查，旨在确定可能导致艾滋病毒易感性增加的因素。 我们还将表征阴茎皮肤和尿道微生物组，并表征炎症水平 在尿道里我们将探讨MMC如何减少HIV感染的可能机制， 通过三个具体目标。目标1将确定包皮环切术和无症状性STI（CT和 HPV）影响尿道免疫环境和微生物组。在目标2中，我们将比较 在MMC前后的冠状沟（CS）微生物组和TEWL中，并评估 无症状CT和HPV感染。这些发现将与 微生物组和尿道中的免疫变化。最后，在目标3中，我们将比较靶细胞、屏障 内外包皮之间的功能、结构屏障蛋白表达和病毒相互作用 并确定无症状性传播感染是否会改变局部粘膜环境。我们 因此，假设内包皮：1）具有更大的渗透性，2）具有降低的 皮肤完整性蛋白，3）含有更多的HIV-1免疫细胞，4）允许更多的HIV附着 和穿透力都比包皮要强这些相互作用可能受到以下因素的影响： 无症状CT和HPV。总的来说，我们的研究结果将提供基础知识， 替代性艾滋病毒预防战略。

HIV acquisition in men through penile exposure is one of the least studied aspects of HIV transmission. Medical Male Circumcision (MMC) has been shown in clinical trials to reduce the risk of HIV infection in heterosexual men. It is not fully known how MMC works to decrease male heterosexual transmission. One possible explanation is that the urethral and skin mucosal barriers of the penis change after MMC to strengthen its defenses against HIV. Another possibility is that the foreskin itself is particularly vulnerable to HIV, having weaker defenses allow the virus to more easily reach susceptible immune target cells. This might especially be true when an uncircumcised man has a sexually transmitted infection (STI) would generate a local immune response and recruitment of susceptible HIV target cells. These possibilities form the basis of this study which will determine how the penile mucosal barriers change after MMC. We will recruit several cohorts of sexually active males between 18-35 years old receiving MMC in Chicago and Cape Town and from an STI clinic in Cape Town. To address the potential role of STIs, we will also enroll males in Cape Town who are asymptomatically positive for Chlamydia Trachimonas (CT) or Human Papilloma Virus (HPV). To monitor a changing local environment, we will follow these participants for 2-6 months after CT treatment or MMC. We will measure changes in penile skin integrity using in vivo monitoring of trans epithelial water loss (TEWL) and collect foreskins to use in laboratory-based investigations aimed at identifying factors that may lead to increased HIV susceptibility. We will also characterize the penile skin and urethral microbiome and characterize inflammation levels in the urethra. We will explore possible mechanisms for how MMC works to decrease HIV acquisition in men through three specific aims. Aim 1 will determine how circumcision and asymptomatic STI (CT and HPV) influence the urethral immune environment and microbiome. In Aim 2, we will compare differences in the coronal sulcus (CS) microbiome and TEWL pre and post MMC, and assess the potential impact of asymptomatic CT and HPV infections on these measurements. These findings will be linked to microbiome and immune changes in the urethra. Finally, in Aim 3, we will compare target cells, barrier function, structural barrier protein expression, and virus interactions between inner and outer foreskin and determine if infection with an asymptomatic STI can alter the local mucosal environment. We therefore hypothesize that the inner foreskin: 1) has greater permeability, 2) has reduced expression of skin integrity proteins, 3) contains more HIV-1 immune cells and 4) allows for greater HIV attachment and penetration, than the outer foreskin. These interactions may be influences by the presence of asymptomatic CT and HPV. Collectively, our results will provide fundamental knowledge to inform alternative HIV prevention strategies.