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

男性通过阴茎接触获得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)已在临床试验中被证明可以降低艾滋病病毒感染的风险 异性恋男人。目前还不完全清楚MMC是如何减少男性异性传播的。 一种可能的解释是MMC后阴茎的尿路和皮肤粘膜屏障发生了变化。 以加强对艾滋病毒的防御。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，使病毒更容易获得敏感的免疫力 目标单元格。尤其是在未割包皮的男性有性传播感染的情况下。 (STI)将产生局部免疫反应和招募敏感的艾滋病毒目标细胞。这些 这种可能性构成了这项研究的基础，它将确定阴茎粘膜屏障是如何变化的。 在MMC之后。我们将招募几个年龄在18-35岁之间的性活跃男性 芝加哥和开普敦的MMC以及开普敦的一家性传播感染诊所。为了解决潜在的作用， 性传播感染，我们还将在开普敦招募无症状衣原体阳性的男性 沙眼单胞菌(CT)或人乳头瘤病毒(HPV)。为了监测不断变化的本地环境，我们将 在CT治疗或MMC治疗后对这些参与者进行2-6个月的跟踪调查。我们将测量阴茎的变化 使用体内监测皮肤完整性的跨上皮水分丢失(TEWL)和收集包皮用于 以实验室为基础的调查，旨在确定可能导致艾滋病毒易感性增加的因素。 我们还将确定阴茎皮肤和尿路微生物群的特征，并确定炎症程度。 在尿道处。我们将探索MMC如何在全球范围内减少HIV感染的可能机制 男人通过三个特定的目标。目标1将确定包皮环切术和无症状性传播感染(CT和 HPV)影响尿路免疫环境和微生物区系。在目标2中，我们将比较差异 在MMC前后的冠沟(CS)微生物组和TEWL中，并评估 无症状的CT和HPV感染的这些测量。这些发现将与 尿路中的微生物群和免疫变化。最后，在目标3中，我们将比较目标细胞、屏障 包皮内外的功能、结构屏障蛋白表达和病毒相互作用 并确定感染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)降低了 皮肤完整性蛋白质，3)含有更多的HIV-1免疫细胞，4)允许更多的HIV附着 和穿透性，而不是外层包皮。这些相互作用可能受存在的影响 无症状的CT和HPV。总而言之，我们的结果将提供基本的知识，以供 替代艾滋病毒预防战略。

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.