The Microbiome and Anal Cancer Pathogenesis in HIV-infected Men who have Sex with Men

项目摘要/摘要 随着抗逆转录病毒药物的出现，艾滋病毒感染者患肛门癌的风险显著增加。 治疗，特别是在感染艾滋病毒的男男性行为者(MSM)中。90%的侵入性肛门 鳞状细胞癌与人类乳头瘤病毒(HPV)感染有关，其中80%-90%是 虽然肛门HPV-16感染在感染HIV的MSM中很常见，但只有一小部分 一小部分受感染的男性曾患上肛门癌。为什么这种情况会发生在一些人身上，而不是其他人身上，这一点尚不清楚。 最近的技术进步使对基因组成进行测序和研究成为可能，或者 “微生物群”，指定植于人体不同部位的微生物群落。的扩展 否则，胃肠道内的共生细菌被认为是导致炎症和 通过多种途径致癌，包括产生超氧阴离子自由基和毒素。这些 失衡与炎症性肠病和结直肠疾病等疾病状态有关。 癌症。 这项研究将确定在肛管微生物群和高致死率之间是否存在类似的关联。 鳞状上皮内病变(HSIL)，浸润性肛门癌的前驱症状。我们将决定 肛管内是否有致炎细菌的聚集和抗炎物质的消耗 细菌与肛门HSIL有关，特别是因为长期慢性炎症已被提出。 作为人乳头瘤病毒致癌过程中的关键介质。因此，我们的具体目标是：1)描述 男男性接触者、HIV感染者、男男性接触者肛门微生物群α和β多样性的差异 有无肛门HSIL的有效ART；以及2)确定肛门成分的具体差异 微生物群之间存在感染HIV、肛门HPV-16感染、男男性接触者对有无肛门HSIL的有效治疗。 我们的结果将有助于我们理解HPV的致癌机制，并可能为我们提供新的 肛门型HSIL的诊断和治疗方法。

PROJECT SUMMARY/ABSTRACT The risk of anal cancer in HIV-infected individuals has markedly increased following the advent of anti-retroviral therapy, especially in HIV-infected men who have sex with men (MSM). 90% percent of invasive anal squamous cell carcinomas are associated with human papillomavirus (HPV) infection, of which 80-90% are associated with HPV type 16. Although anal HPV-16 infection is common in HIV-infected MSM, only a small fraction of infected men ever develops anal cancer. Why this occurs in some but not others is unknown. Recent advances in technology have made it feasible to sequence and study the genetic composition, or “microbiome”, of the community of microbes that colonize different parts of the human body. The expansion of otherwise commensal bacteria within the gastrointestinal tract is postulated to contribute to inflammation and carcinogenesis via a variety of pathways including the production of superoxide radicals and toxins. These imbalances have been associated with disease states such as inflammatory bowel disease and colorectal cancer. This study will determine whether a similar association exists between the anal canal microbiome and high- grade squamous intraepithelial lesions (HSIL), the precursor to invasive anal cancer. We will determine whether enrichment of the anal canal with pro-inflammatory bacteria and depletion of anti-inflammatory bacteria is associated with anal HSIL, particularly because long-term chronic inflammation has been proposed as a key mediator in HPV cancer pathogenesis. Accordingly our specific aims are: 1) To characterize the differences in α and β-diversity of the anal microbiome in HIV-infected, anal HPV-16 infected, MSM on effective ART with and without anal HSIL; and 2) To identify specific differences in the composition of the anal microbiome between HIV-infected, anal HPV-16 infected, MSM on effective ART with and without anal HSIL. Our results will contribute to our understanding of HPV carcinogenesis and may potentially provide new approaches to diagnosis and treatment of anal HSIL.