Penile viral and bacterial microbiome, inflammation and HIV susceptibility

粘膜微生物组在确定感染艾滋病毒的风险方面起着关键作用。阴茎厌氧细菌 丰度与阴茎细胞因子浓度相关，细胞因子与HIV靶细胞相关 包皮中的密度。此外，厌氧菌丰度和阴茎细胞因子浓度也有关联。 随着艾滋病毒感染发生率的增加。因此，阴茎微生物群的改变是可能的 由此产生的炎症变化可能会增加感染艾滋病毒的风险。同样，阴道微生物群落与 高度多样性或以厌氧或兼性细菌为主的细菌使女性感染艾滋病毒的风险更高 并与高生殖器炎症有关，后者被认为能吸引或激活HIV靶标。 细胞在粘膜或改变粘膜的完整性。除了细菌，粘膜微生物群还包含 病毒，以及一个社区的变化可能会调节另一个社区的变化。肠道细菌体的多样性反映了 在病毒体中，感染原核生物和真核细胞的病毒的集合，这些多样性模式是 由噬菌体驱动，而不是由真核病毒驱动。噬菌体种群的扩张，病毒 感染细菌，一直与免疫细胞扩张和肠道炎症增加有关。病毒式传播 群落可以通过直接激活或通过修改细菌间接影响宿主免疫。 社区。然而，阴茎病毒体对细菌群落、免疫和艾滋病毒的影响 敏感度尚不清楚。 CHAPS研究将13-24岁的年轻男性随机分为安慰剂和不同剂量的口服 在包皮环切术前使用抗逆转录病毒药物，为我们提供了解决这些知识中的一些问题的独特机会 差距。登记工作已经完成，储存了144份包皮和相应的阴茎拭子， 提供有价值的数据，包括体外艾滋病毒易感性和局部组织基因表达。我们将延长 这项研究是为了验证我们的假设，即阴茎病毒和细菌之间存在关联 微生物区系，阴茎厌氧细菌的相对丰度调节上皮炎症 和CD4目标细胞可获得性，因此艾滋病毒易感性具有以下具体目标： 目的1：评估阴茎粘膜的跨王国相互作用。假设：病毒和细菌 阴茎的微生物区系是相互关联的。 目的2：探讨细菌微生物群、上皮细胞炎症、靶标之间的相互作用。 细胞可获得性和艾滋病毒易感性。阴茎厌氧细菌相对丰度假说 调节上皮炎症、CD4靶细胞的可获得性，从而调节HIV的易感性。 我们提出了一项极具创新性的独特研究，以回答有关阴茎微生物组的重要问题。 和艾滋病毒易感性，这可能导致改善预防干预措施，如益生菌或抗菌素 发炎药，用于未割包皮的男性。

The mucosal microbiome plays a key role in determining risk for HIV acquisition. Penile anaerobic bacterial abundance correlates with penile cytokine concentrations, and cytokines are associated with HIV target cell density in the foreskin. Furthermore, anaerobe abundance and penile cytokine concentrations are associated with increased incidence of HIV infection. Thus, it is plausible that alterations in the penile microbiome with resultant inflammatory changes may increase the risk of HIV. Similarly, vaginal microbial communities with high diversity or those dominated by anaerobic or facultative bacteria render women at higher risk of HIV acquisition and are associated with high genital inflammation, which is thought to attract or activate HIV target cells in the mucosa or alter mucosal integrity. In addition to bacteria, the mucosal microbiome also contains viruses, and shifts in one community may modulate shifts in the other. The gut bacteriome diversity is mirrored in the virome, the collection of pro- and eukaryote-infecting viruses, and that these patterns of diversity are driven by bacteriophages, not by eukaryotic viruses. Expansion of bacteriophage populations, viruses that infect bacteria, has been linked to immune cell expansion and increased inflammation in the gut. Viral communities can influence host immunity by direct activation, or indirectly by modifying the bacterial community. However, the impact of the penile virome on bacterial communities, immunity and HIV susceptibility are unknown. The CHAPS study, which is randomizing young men aged 13-24 years to placebo versus various oral doses of antiretrovirals prior to circumcision, affords us the unique opportunity to address some of these knowledge gaps. Enrolment is complete, and 144 foreskins and corresponding penile swabs have been stored, with valuable data including ex vivo HIV susceptibility and local tissue gene expression available. We will extend the study to test our hypothesis that there is an interlinkage between penile viral and bacterial microbiota, and that penile anaerobic bacteria relative abundance modulates epithelial inflammation and CD4 target cell availability, and therefore HIV susceptibility with the following Specific Aims: Aim 1: To assess inter-kingdom interactions at the penile mucosa. Hypothesis: The viral and bacterial microbiota of the penis are interrelated. Aim 2: To evaluate the interaction between the bacterial microbiome, epithelial inflammation, target cell availability and HIV susceptibility. Hypothesis Penile anaerobic bacterial relative abundance modulates epithelial inflammation, CD4 target cell availability, and hence HIV susceptibility. We propose a highly innovative, unique study to answer important questions regarding the penile microbiome and HIV susceptibility, that could lead to improved prevention interventions, such as probiotics or anti- inflammatories, for uncircumcised males.