Penile viral and bacterial microbiome, inflammation and HIV susceptibility

粘膜微生物组在确定艾滋病毒感染风险方面发挥着关键作用。阴茎厌氧菌 丰度与阴茎细胞因子浓度相关，细胞因子与 HIV 靶细胞相关 包皮的密度。此外，厌氧菌丰度和阴茎细胞因子浓度相关 随着艾滋病毒感染率的增加。因此，阴茎微生物组的改变似乎是合理的 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 高度多样性或以厌氧菌或兼性细菌为主的细菌使女性感染艾滋病毒的风险更高 获得性并与高度生殖器炎症相关，这被认为可以吸引或激活 HIV 目标 粘膜细胞或改变粘膜完整性。除细菌外，粘膜微生物组还含有 病毒，一个群落的变化可能会调节另一个群落的变化。反映了肠道细菌组的多样性 在病毒组中，原核生物和真核生物感染病毒的集合，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、病毒的扩张 感染细菌，与免疫细胞扩张和肠道炎症增加有关。病毒式 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，阴茎病毒组对细菌群落、免疫力和艾滋病毒的影响 敏感性未知。 CHAPS 研究将 13-24 岁的年轻男性随机分为安慰剂组和各种口服剂量组 包皮环切术前抗逆转录病毒药物的使用，为我们提供了解决其中一些知识的独特机会 差距。登记完成，已储存包皮及相应阴茎拭子144份， 有价值的数据包括可用的离体艾滋病毒易感性和局部组织基因表达。我们将延长 这项研究旨在检验我们的假设，即阴茎病毒和细菌之间存在相互联系 微生物群，阴茎厌氧菌的相对丰度调节上皮炎症 和 CD4 靶细胞的可用性，以及 HIV 易感性，具体目标如下： 目标 1：评估阴茎粘膜领域间的相互作用。假设：病毒和细菌 阴茎的微生物群是相互关联的。 目标 2：评估细菌微生物组、上皮炎症、靶标之间的相互作用 细胞可用性和艾滋病毒易感性。假设阴茎厌氧细菌相对丰度 调节上皮炎症、CD4 靶细胞可用性，从而调节 HIV 易感性。 我们提出了一项高度创新、独特的研究来回答有关阴茎微生物组的重要问题 和艾滋病毒易感性，这可能会导致改善预防干预措施，例如益生菌或抗- 炎症，适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.