Molecular Epidemiology and Natural History of SIVcpz

描述（由申请人提供）：修订后的更新申请的重点仍然围绕野生黑猩猩SIVcpz感染的自然史。在上一个预算期间，我们开发了非侵入性（粪便和尿液）SIVcpz检测方法，并使用这些方法来表征整个赤道非洲野生猿种群中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社区（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（如HIV-1）已经失去了其Nef蛋白的重要功能（Cell 2006; PLoS Pathogens 2008）。29篇出版物总结了这些和其他结果（包括自上次提交以来发表的3篇）。我们还在两个习惯性社区中发起了SIVcpz的第一个自然历史研究（人口规模约90）在贡贝国家公园，并发现（i）SIVcpz流行率增加了一倍以上，在过去的七年，（ii）SIVcpz感染黑猩猩有显着更高的死亡率（18.7至20.6倍增加的死亡危险; p<0.0001），和（iii）两个SIVcpz感染的黑猩猩死于特征性的艾滋病样免疫病理学。这些发现提供了第一个证据，表明SIVcpz感染在野生黑猩猩中是致病性的，因此与所有自然SIV感染都是非致病性的流行观点背道而驰。鉴于这些有趣的发现，我们建议扩大我们的自然史研究在贡贝，表征病毒和宿主的SIVcpz致病性的决定因素，并确定其他病原体的合并感染是否影响SIVcpz的发病率和死亡率。具体目标包括：1。将SIVcpz的自然历史研究扩展到所有三个贡贝社区。我们将确定SIVcpz的流行率和发病率，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相关的死亡率在一个更大的黑猩猩群体。2.阐明SIVcpz致病的免疫病理学机制。我们将进行健康调查和寄生虫学研究，并对研究期间死亡的所有猿类进行尸检分析。尸检标本的详细免疫组织化学和病毒学分析将确定SIVcpz导致CD 4 T细胞耗竭、淋巴组织破坏和免疫激活的程度。3.阐明SIVcpz致病性的病毒学机制。我们将产生感染性分子克隆选择SIVcpz菌株，表征其复制健身和相对毒力，并确定SIVcpz进化的模式和速度。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，我们将筛选贡贝黑猩猩的STLV，ChHBV和腺病毒，并确定这些感染是否以及在何种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/艾滋病是近代历史上出现的最重要的传染病之一。该应用将定义HIV-1的猿猴前体SIVcpz的分子生态学和自然感染史。阐明SIV在天然和非天然宿主中致病性（或缺乏致病性）的决定因素是当前AIDS研究的高度优先领域，因为治疗和疫苗策略考虑疾病的改善和预防是期望的结果。野生黑猩猩的SIVcpz感染代表了这个难题的关键部分。

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.