Molecular Epidemiology and Natural History of SIVcpz

项目摘要 修改后的续订申请的重点仍然是SIVcpz感染的自然病史 在野生黑猩猩身上。在上一个预算期间，我们开发了非侵入性(基于粪便和尿液) SIVcpz检测方法及其用于描述野生动物SIVcpz的分子流行病学 赤道非洲的类人猿种群(《自然》2004年；《科学》2006年)。我们还追踪到了 喀麦隆南部不同黑猩猩群落的大流行和非大流行HIV-1(科学 2006)，在野生大猩猩中发现了类似HIV-1的病毒(自然2006)，并发现SIVcpz(类似HIV-1) 已经失去了其Nef蛋白的一个重要功能(Cell 2006；PLoS Pathogens 2008)。这些和其他发现 摘要载于29份出版物(包括自上次提交以来发表的3份)。我们还发起了第一个 贡贝国家公园两个习性群落(种群规模~90)中SIVcpz的自然历史研究 并发现(I)SIVcpz患病率在过去七年中增加了一倍多，(Ii)SIVcpz 被感染的黑猩猩的死亡率明显更高(死亡率增加18.7到20.6倍 0.0001)，以及(Iii)两只感染了SIVcpz的黑猩猩死于 典型的艾滋病样免疫病理学。这些发现提供了SIVcpz感染是第一个证据 在野生黑猩猩中致病，因此与流行的观点背道而驰，即所有自然的SIV感染都是 非致病的。鉴于这些耐人寻味的发现，我们建议在贡贝扩大我们的自然历史研究， 确定SIVcpz致病性的病毒和宿主决定因素，并确定是否由其他 病原体影响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所有三个贡贝社区。我们将决定 SIVcpz患病率和发病率、垂直和水平传播频率、SIVcpz对 在更大的黑猩猩群体中，生殖行为和成功以及与SIVcpz相关的死亡率。 2.阐明SIVcpz致病的免疫病理机制。我们将进行 健康调查和寄生虫学研究，以及对研究期间死亡的所有类人猿的尸检分析 句号。对尸检样本进行详细的免疫组织化学和病毒学分析将确定 SIVcpz在一定程度上会导致CD4T细胞耗尽、淋巴组织破坏和免疫激活。 3.阐明SIVcpz致病的病毒学机制。我们会产生传染性 选择SIVcpz菌株的分子克隆，表征它们的复制适合性和相对毒力，以及 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，我们将对冈贝黑猩猩进行STLV、ChHBV腺病毒的筛查，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。

Project Summary 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 who 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.