Biologic Determinants of the Natural History of AIDS-Defining Cancers in Uganda

描述（由申请人提供）：癌症已成为美国长期HIV感染的最常见并发症之一，并且可能成为撒哈拉以南非洲地区更大的威胁，因为抗逆转录病毒治疗的延迟和不完全获得，病毒致癌物的高患病率，以及由于儿科HIV感染，一个人可能处于发展癌症的风险中的更多年数。在该地区，三种“艾滋病定义癌症”，包括卡波西肉瘤（KS）、非霍奇金淋巴瘤（NHL）和浸润性宫颈癌（ICC），仍然是整个人口中最常见的癌症。在过去的十年中，弗雷德哈钦森癌症研究中心与乌干达癌症研究所合作，对感染相关的癌症进行合作研究和培训;并确定HIV相关恶性肿瘤（HIVAM）的自然史，生物学和治疗。这项工作表明，与类似的艾滋病毒阴性癌症患者相比，艾滋病毒感染癌症患者的死亡风险显著增加，并且对治疗的反应在患有三种ADC的艾滋病毒感染者中差异很大。在本研究中，我们试图通过以下具体目标来理解乌干达ADC差异自然史的生物学基础：1）表征两种病毒致癌基因，人疱疹病毒-8（HHV-8）和人乳头瘤病毒（HPV）之间的病毒遗传多样性，并开始探索遗传变异与KS和ICC的自然史之间的关系; 2）描述艾滋病定义的恶性肿瘤患者开始抗逆转录病毒治疗和化疗后细胞免疫反应的演变; 3）通过优化受过艾滋病毒/艾滋病和疟疾研究培训的乌干达人的科学领导能力，扩大在乌干达进行艾滋病毒/艾滋病和疟疾最先进转化研究的能力，为乌干达的HIVAM研究维持一个独特而非凡的生物储存库，扩大ADC患者的入组，以进行自然史的转化研究， 他们的恶性肿瘤，并提供跨两大洲的合作生物医学研究的行政支持。

DESCRIPTION (provided by applicant): Cancer has become one of the most common complications of long-term HIV infection in the US, and may come to be an even greater threat in sub-Saharan Africa because of the delayed and incomplete access to antiretroviral therapy, the high prevalence of viral oncogens, and a larger number of years a person may be at risk for developing cancer due to pediatric HIV infection. In this region, the three "AIDS-Defining Cancers", including Kaposi sarcoma (KS), non-Hodgkin Lymphoma (NHL), and invasive cervical cancer (ICC), remain among the most common cancers in the entire population. Over the past decade, the Fred Hutchinson Cancer Research Center has collaborated with the Uganda Cancer Institute to conduct collaborative research and training on infection-related cancers; and define the natural history, biology and treatment of HlV-associated malignancies (HIVAM). This work has revealed HIV-infected individuals with cancer are at significantly increased risk of death when compared with similar HIV-negative persons with cancer, and that the response to therapy varies dramatically within HIV-infected persons with the three ADCs. In the current proposal, we seek to understand the biologic basis for the differential natural history of ADCs in Uganda through the following Specific Aims: 1) To characterize the viral genetic diversity among two viral oncogens, human herpesvirus-8 (HHV-8) and human papillomavirus (HPV), and begin to explore the relationship between genetic variants and the natural history of KS and ICC, respectively; 2) To describe the evolution of the cellular immune response among persons with AlDS-defining malignancies who initiate antiretroviral therapy and chemotherapy; 3) To expand the capacity to conduct state-of-the-art translational research in HIVAM in Uganda through optimizing scientific leadership among Ugandans who have been trained in HIVAM research, maintaining a unique and extraordinary biorepository for the study of HIVAM in Uganda, expanding the enrollment of patients with ADCs into translational studies of the natural history of their malignancies, and providing the administrative support for collaborative biomedical research across two continents.