Project 1: Exploring viral and immunological factors of HPV associated cancers in PLWH and its relation to survival

项目摘要-项目1 艾滋病毒感染者（PLWH）的癌症发病率明显高于无艾滋病毒感染者， HPV引起的癌症（宫颈癌、外阴癌、肛门癌、阴茎癌和口咽癌）。免疫力的改变，不仅仅是 免疫缺陷，是一个提出的机制，推动这种过度的风险和显着更糟糕的结果 与没有艾滋病毒的个体相比，在癌症诊断后观察到。肿瘤病毒和免疫环境 可能是导致艾滋病病毒携带者患癌差异的主要因素。然而，很少有研究 研究了HIV引起的癌症负担差异的肿瘤因素（病毒和免疫）， 目前的状况，需要制定改进的癌症预防和治疗策略PLWH的信息。 目前还没有最佳的方法来筛选或治疗低和中水平PLWH中HPV相关的癌症。 低收入国家（LMIC），癌症发病率在全球范围内不断增加。除了宫颈癌，HPV- 在撒哈拉以南非洲（SSA）的艾滋病毒携带者中，相关癌症的研究不足。组合策略 放化疗和免疫疗法正在改变癌症护理并提高生存率， 也有利于PLWH。然而，很少有人知道1）肿瘤的免疫景观之间发展PLWH 和2）免疫疗法改善该人群中癌症结果的益处。 我们的总体目标是为HPV相关疾病的有效预防和治疗策略的发展提供信息， 撒哈拉以南非洲艾滋病毒携带者中的癌症。我们将研究与HPV相关的病毒和肿瘤免疫因子- 癌症和治疗结果，并提出了一个多方面的方法来研究病毒和免疫 景观利用病毒和免疫分析工具和高维技术1，2.具体而言，我们将： 目的1：估计PLWH和HIV未感染者中HPV引起的肿瘤的可归因比例 患者这一目的验证了PLWH在所有肿瘤中HPV基因型的多样性更大的假设。 类型，HPV合并感染的比例较高，具有生物活性HPV的肿瘤比例较高 与未感染艾滋病毒的患者相比。 目的2：表征HPV相关癌症的肿瘤免疫景观。这一目标验证了这一假设 与未感染HIV的患者相比，PLWH患者的肿瘤中存在一个更具抑制性的肿瘤微环境， 尽管浸润性CD 8 + T细胞的比例较高，但这些细胞将终末分化， 疲惫不堪，功能失调 目的3：研究HIV状态与HPV相关癌症治疗结果之间的关系。 这一目标验证了以下假设：与未感染艾滋病毒的人相比，艾滋病毒携带者的死亡率较高， 肿瘤微环境将是生存结果的重要决定因素。

PROJECT SUMMARY – PROJECT 1 People living with HIV (PLWH) have significantly higher cancer incidence compared to people without HIV for cancers caused by HPV (cervical, vulvar, anal, penile, and oropharyngeal). Altered immunity, not simply immunodeficiency, is one proposed mechanism driving this excess risk and the significantly worse outcomes observed following a cancer diagnosis compared to individuals without HIV. The tumor viral and immune milieu are likely major factors contributing to these cancer disparities among PLWH. However, few studies have examined the tumor factors (viral and immune) that underlie differences in the cancer burden by HIV status, information needed to develop improved cancer prevention and treatment strategies for PLWH. Currently there is no optimal method to screen for or treat HPV-related cancers among PLWH in low- and middle- income countries (LMICs), cancers that are increasing in incidence globally. Other than cervical cancer, HPV- related cancers are understudied among PLWH in sub-Saharan Africa (SSA). Combination strategies of chemoradiation and immunotherapy are transforming cancer care and increasing survival, treatments that may also benefit PLWH. However, little is known of 1) the immune landscape of tumors that develop among PLWH and 2) the benefit of immunotherapies to improve cancer outcomes among this population. Our overall goal is to inform the development of effective prevention and treatment strategies for HPV-related cancers among PLWH in SSA. We will study the viral and tumor immune factors that are associated with HPV- cancers and treatment outcomes and propose a multifaceted approach to study both the viral and immune landscape utilizing viral and immune profiling tools and high-dimensional technologies1,2. Specifically, we will: Aim 1: Estimate the attributable fraction of tumors caused by HPV among PLWH and HIV uninfected patients. This aim tests the hypothesis that PLWH will have a larger diversity of HPV genotypes across all tumor types, a higher proportion of HPV co-infections, and higher proportion of tumors with biologically active HPV compared to HIV uninfected patients. Aim 2: Characterize the tumor immune landscape of HPV-related cancers. This aim tests the hypothesis that a more suppressive tumor microenvironment will be present in tumors of PLWH compared to HIV uninfected patients and that despite a higher proportion of infiltrating CD8+ T cells, these will be terminally differentiated, exhausted, and dysfunctional. Aim 3: Investigate the association between HIV status and treatment outcomes for HPV-related cancers. This aim tests the hypothesis that PLWH will have a higher mortality compared to persons without HIV and the tumor microenvironment will be an important determinant of survival outcomes.