Molecular Epidemiology and Natural History of SIVcpz

描述（由申请人提供）：本次修订更新申请的重点仍然集中在野生黑猩猩SIVcpz感染的自然史上。在上一个预算期内，我们开发了非侵入性（基于粪便和尿液）SIVcpz检测方法，并利用这些方法表征了整个赤道非洲野生猿类种群中SIVcpz的分子流行病学（Nature 2004; Science 2006）。我们还将大流行和非大流行HIV-1的起源追溯到喀麦隆南部不同的黑猩猩群落（Science 2006），在野生大猩猩中发现了HIV-1 o组样病毒（Nature 2006），并发现SIVcpz（与HIV-1一样）失去了其Nef蛋白的一个重要功能（Cell 2006; PLoS Pathogens 2008）。这些和其他调查结果摘要载于29份出版物（包括自上次提交以来出版的3份）。我们还在贡贝国家公园的两个习惯群落（种群规模约为90）中发起了SIVcpz的第一次自然历史研究，发现(i) SIVcpz的患病率在过去7年中增加了一倍多，（ii） SIVcpz感染的黑猩猩的死亡率明显高于未感染的对照组（死亡风险增加18.7至20.6倍，p<0.0001）， （iii）两只感染SIVcpz的黑猩猩死于典型的艾滋病样免疫病理。这些发现提供了第一个证据，证明SIVcpz感染在野生黑猩猩中是致病性的，从而推翻了所有自然SIV感染都是非致病性的普遍观点。鉴于这些有趣的发现，我们建议扩大我们在贡贝的自然史研究，表征SIVcpz致病性的病毒和宿主决定因素，并确定其他病原体的共同感染是否影响SIVcpz的发病率和死亡率。具体目标包括：1。将我们对SIVcpz的自然历史研究扩展到贡贝的三个社区。我们将在更大的黑猩猩群体中确定SIVcpz的患病率和发病率，垂直和水平传播的频率，SIVcpz对生殖行为和成功的影响，以及SIVcpz相关的死亡率。2. 目的：阐明SIVcpz致病性的免疫病理机制。我们将对研究期间死亡的所有类人猿进行健康调查和寄生虫学研究，以及验尸分析。尸检标本的详细免疫组织化学和病毒学分析将确定SIVcpz在多大程度上导致CD4 T细胞耗竭、淋巴组织破坏和免疫激活。3. 目的：阐明SIVcpz致病性的病毒学机制。我们将为选择的SIVcpz菌株生成感染性分子克隆，表征它们的复制适应性和相对毒力，并确定SIVcpz的进化模式和速度。4. 确定其他病毒感染对黑猩猩发病率和死亡率的影响。使用非侵入性方法，我们将筛查贡贝黑猩猩的STLV， ChHBV和腺病毒，并确定这些感染是否以及在多大程度上影响黑猩猩的发病率和死亡率。公共卫生相关性：艾滋病毒/艾滋病是近年来出现的最重要的传染病之一。该应用程序将定义SIVcpz的分子生态学和自然感染史，SIVcpz是HIV-1的类人猿前体。在自然和非自然宿主中阐明SIV致病性（或缺乏致病性）的决定因素是当前艾滋病研究的一个高度优先领域，因为治疗和疫苗战略认为改善疾病和预防是一个理想的结果。野生黑猩猩感染SIVcpz是这个谜题的关键部分。

DESCRIPTION (provided by applicant): The focus of this revised renewal application remains centered around the natural history of SIVcpz infection in wild chimpanzees. In the previous budget period, we developed non-invasive (fecal and urine based) SIVcpz detection methods and used these to characterize the molecular epidemiology of SIVcpz in wild-living ape populations throughout equatorial Africa (Nature 2004; Science 2006). We also traced the origin of pandemic and non-pandemic HIV-1 to distinct chimpanzee communities in southern Cameroon (Science 2006), discovered HIV-1 group O-like viruses in wild gorillas (Nature 2006), and found that SIVcpz (like HIV-1) has lost an important function of its Nef protein (Cell 2006; PLoS Pathogens 2008). These and other findings are summarized in 29 publications (including 3 published since the last submission). We also initiated the first natural history study of SIVcpz in two habituated communities (population size ~90) in Gombe National Park and found that (i) SIVcpz prevalence has more than doubled over the past seven years, (ii) SIVcpz infected chimpanzees have a significantly higher mortality rate (18.7 to 20.6-fold increased death hazard; p<0.0001) than uninfected controls, and (iii) two SIVcpz infected chimpanzees died with characteristic AIDS-like immunopathology. These findings provide the first evidence that SIVcpz infection is pathogenic in wild chimpanzees, and thus run counter the prevailing view that all natural SIV infections are non-pathogenic. Given these intriguing findings, we propose to expand our natural history studies in Gombe, characterize viral and host determinants of SIVcpz pathogenicity, and determine if co-infections by other pathogens influence SIVcpz morbidity and mortality. Specific Aims include: 1. To expand our natural history studies of SIVcpz to all three Gombe communities. We will determine SIVcpz prevalence and incidence rates, frequencies of vertical and horizontal transmission, SIVcpz impact on reproductive behavior and success, as well as SIVcpz associated mortality in a larger group of chimpanzees. 2. To elucidate the immunopathological mechanisms underlying SIVcpz pathogenicity. We will conduct health surveys and parasitology studies, as well as post mortem analyses on all apes that die during the study period. Detailed immunohistochemical and virological analyses of necropsy specimens will determine to what extent SIVcpz causes CD4 T cell depletion, lymphatic tissue destruction and immune activation. 3. To elucidate the virological mechanisms underlying SIVcpz pathogenicity. We will generate infectious molecular clones for select SIVcpz strains, characterize their replication fitness and relative virulence, and determine the pattern and rate of SIVcpz evolution. 4. To determine the impact of other viral infections on chimpanzee morbidity and mortality. Using non- invasive methods, we will screen Gombe chimpanzees for STLV, ChHBV and adenoviruses and determine whether and to what extent these infections influence chimpanzee morbidity and mortality. PUBLIC HEALTH RELEVANCE: HIV/AIDS ranks as one of the most important infectious diseases to have emerged in recent history. This application will define the molecular ecology and natural infection history of SIVcpz, the simian precursor of HIV-1. Elucidation of the determinants of SIV pathogenicity (or lack thereof) in natural and non-natural hosts is a high priority area in current AIDS research, since therapeutic and vaccine strategies consider amelioration of disease and prevention a desired outcome. SIVcpz infection of wild-living chimpanzees represents a critical piece in this puzzle.