Studies of the precursor of the human AIDS virus in its natural chimpanzee host

 描述(申请人提供)：黑猩猩免疫缺陷病毒(SIVcpz)是人类免疫缺陷病毒1型(HIV-1)的前身，HIV-1是艾滋病大流行的原因(1-3)。在过去的十年里，我们的团队研究了野生黑猩猩的SIVcpz感染，将非侵入性病毒检测与黑猩猩的行为、生活史、生育力和死亡率的研究相结合(1-60)。这些研究为SIVcpz的生物学和致病性(4-6)、其流行率和地理分布(7-9)、其人畜共患病潜力(8、10-12)以及其对抗强大的人类限制因素的能力(12-19)提供了前所未有的洞察力。我们还研究了野生黑猩猩(20-42)的生态、行为、遗传学和种群历史，在它们的粪便样本中发现了新的病毒(43-45)、寄生虫(46-50)和微生物区系(51-56)，包括其他主要人类病原体的前体(46、47、57)。大部分工作是在贡贝国家公园进行的，这是世界上唯一一个可以近距离研究习惯性黑猩猩SIVcpz感染的野外地点。在这项申请中，我们建议利用这些发现，其中许多现在才开始取得成果，并继续对感染SIVcpz的野生类人猿进行非侵入性调查，以帮助它们生存并提高人类健康。我们的工作假设是，对人类艾滋病病毒前体在其自然黑猩猩宿主中的研究将继续揭示对艾滋病毒/SIV发病机制的关键新见解，并导致新的干预措施，对人类和黑猩猩都有利。利用贡贝独特的生态、现有的知识库和研究基础设施，我们将继续研究SIVcpz的病原体及其对三个居住的黑猩猩社区的影响，首次评估旨在减少SIVcpz传播的干预措施的必要性和可行性(目标1)。我们还将把实地研究扩展到大马哈尔生态系统(GME)，该生态系统是约2500只高度濒危稀树草原黑猩猩的家园，以确定SIVcpz在多大程度上渗透到了这个更大、更多样化的种群中(目标1)。为了确定人畜共患传播的新障碍，我们将确定为什么每次APE病毒跨越物种屏障进入人类时都需要Gag蛋白的适应，并阐明病毒基质蛋白(Gag-30)第30位的一个特定氨基酸残基如何增加人类CD4+T细胞对1型干扰素(IFN)的SIVcpz抵抗力(目标#2)。最后，我们将探索有效中和不同HIV-1毒株的单抗和免疫粘附素是否可以用于载体免疫预防和/或治疗以对抗SIVcpz感染(目标#3)。这些目标的实现不仅将独特地补充正在进行的HIV-1致病机理、预防和治疗研究，而且将为旨在将针对HIV-1感染者开发的干预措施转化为SIVcpz感染黑猩猩的可行性研究奠定基础。

 DESCRIPTION (provided by applicant): Simian immunodeficiency virus of chimpanzees (SIVcpz) is the precursor of human immunodeficiency virus type 1 (HIV-1), the cause of the AIDS pandemic (1-3). For the past decade, our group has studied SIVcpz infection of wild-living chimpanzees, combining non-invasive virus detection with studies of chimpanzee behavior, life history, fertility and mortality (1-60). These investigations have provided unprecedented insight into the biology and pathogenicity of SIVcpz (4-6), its prevalence and geographic distribution (7-9), its zoonotic potential (8, 10-12), and its ability to counteract potent human restriction factos (12-19). We also examined the ecology, behavior, genetics and population history of wild chimpanzees (20-42), and discovered novel viruses (43-45), parasites (46-50) and microbiota (51-56) in their fecal samples, including the precursors of other major human pathogens (46, 47, 57). Most of this work was conducted in Gombe National Park, the only field site in the world where SIVcpz infection can be studied in habituated chimpanzees at close range. In this application, we propose to capitalize on these findings, many of which are only now coming to fruition, and to continue to conduct non-invasive investigations of SIVcpz infected wild-living apes to aid their survival as well as to enhance human health. Our working hypothesis is that studies of the precursor of the human AIDS virus in its natural chimpanzee host will continue to reveal critical new insight into HIV/SIV pathogenesis and lead to new interventions that will benefit both humans and chimpanzees. Taking advantage of the unique ecology, existing knowledge base and research infrastructure in Gombe, we will continue to study the pathobiology of SIVcpz and its impact on the three resident chimpanzee communities, assessing for the first time the necessity and feasibility of interventions aimed at reducing SIVcpz transmission (Aim #1). We will also expand our field studies to the Greater Mahale Ecosystem (GME), which is home to ~2,500 highly endangered savanna chimpanzees, to determine to what extent SIVcpz has penetrated this much larger and more diverse population (Aim #1). To identify new barriers of zoonotic transmission, we will determine why adaptation of the Gag protein was required each time ape viruses crossed the species barrier to humans, and elucidate how one particular amino acid residue at position 30 of the viral matrix protein (Gag-30) increases SIVcpz resistance to type 1 interferons (IFNs) in human CD4+ T cells (Aim #2). Finally, we will explore whether monoclonal antibodies and immunoadhesins that potently neutralize diverse strains of HIV-1 can be used for vectored immunoprophylaxis and/or therapy to combat SIVcpz infection (Aim #3). Execution of these aims will not only uniquely complement ongoing pathogenesis, prevention and cure research in HIV-1, but will lay the groundwork for feasibility studies aimed at translating interventions developed for HIV-1 infected humans to benefit SIVcpz infected chimpanzees.