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

对黑猩猩天然宿主中人类艾滋病病毒前体的研究

• 批准号: 9186500
• 负责人: Beatrice H Hahn
• 金额: $ 67.26万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186500
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Amino Acids; Antibodies; Behavior; Behavioral Genetics; Binding; Biology; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cells; Central Africa; Communities; Complement; Consensus; Data; Ecology; Ecosystem; Evolution; Exhibits; Feasibility Studies; Fertility; Future; Genes; Geographic Distribution; Goals; HIV; HIV-1; Health; Home environment; Human; Immunogenetics; Immunologic Deficiency Syndromes; Infection; Interferons; Intervention; Investigation; Lead; Life Cycle Stages; Longevity; Methods; Molecular Epidemiology; Monitor; Mono-S; Monoclonal Antibodies; Morbidity - disease rate; Natural History; Pan Genus; Parasites; Pathogenesis; Pathogenicity; Pongidae; Population; Population Heterogeneity; Positioning Attribute; Prevalence; Prevention; Prevention strategy; Proteins; Proteome; Recombinant adeno-associated virus (rAAV); Recording of previous events; Reproduction; Research; Research Infrastructure; Resistance; SIV; Sampling; Site; Small Interfering RNA; Tanzania; Testing; Therapeutic; Time; Translating; Viral Load result; Viral Matrix Proteins; Virus; Work; Zoonoses; arginyllysine; combat; efficacy testing; field study; fitness; gag Gene Products; humanized mouse; immunoprophylaxis; improved; in vivo; insight; knock-down; knowledge base; leucylmethionine; life history; man; microbiota; mimetics; mimicry; mortality; neutralizing antibody; noninvasive diagnosis; novel; novel strategies; novel virus; offspring; overexpression; pandemic disease; pathogen; pre-clinical; prevent; public health relevance; receptor; safety testing; transcriptomics; transmission process; treatment strategy; vector; viral detection; viral transmission

 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.

 描述（由应用提供）：黑猩猩（SIVCPZ）的猿猴免疫缺陷病毒是人类免疫缺陷病毒1型（HIV-1）的前体，这是艾滋病大流行的原因（1-3）。在过去的十年中，我们的小组研究了SIVCPZ的野生生命的黑猩猩感染，将非侵入性病毒检测与黑猩猩行为，生活史，生育能力和死亡率的研究相结合（1-60）。这些研究提供了对SIVCPZ（4-6）的生物学和致病性，其流行和地理分布（7-9）的生物学和致病性的史无前例的见解（7-9），其人畜共患潜力（8，10-12）及其抵消潜在的人类限制事实的能力（12-19）。我们还研究了野生黑猩猩（20-42）的生态，行为，遗传学和人口史，并发现了新型病毒（43-45），寄生虫（46-50）和微生物群（51-56）在其粪便样本中，包括其他主要人类病原体的前体（46，47，47，47，57）。这项工作的大部分是在Gombe国家公园进行的，Gombe国家公园是世界上唯一可以在近距离习惯的黑猩猩研究SIVCPZ感染的现场。在此应用程序中，我们建议利用这些发现，其中许多发现直到现在才得以实现，并继续对SIVCPZ感染的野生活着的猿类进行非侵入性调查，以帮助其生存和增强人类健康。我们的工作假设是，在其自然的黑猩猩宿主中对人类艾滋病病毒的前体的研究将继续揭示对HIV/SIV发病机理的关键新见解，并导致新的干预措施，从而使人类和黑猩猩都受益。利用Gombe的独特生态学，现有的知识库和研究基础设施，我们将继续研究SIVCPZ的病理学及其对三个常驻Chinazee社区的影响，这是首次评估旨在减少SIVCPZ传播的干预措施的必要和可行性（AIM AIM＃1）。我们还将将我们的现场研究扩展到大型Mahale生态系统（GME），该系统拥有约2500种高度濒危的Savanna Chimpanzees，以确定SIVCPZ在多大程度上渗透到了这个更大和更多的潜水员人群（AIM＃1）。为了确定人畜共动性传播的新障碍，我们将确定为什么每次猿类病毒跨越了人类的物种屏障，并阐明了一个特定的氨基酸在病毒基质蛋白（GAG-30）的位置30时如何保留一个特定的氨基酸在人类中会增加SIVCPZ抗性1型外科（IFNS（IFNS）在人类CD4+ t typer type）（IFNS）（IM CD4+ t）（AIM AIM AIM AIM AIM），为什么需要对GAG蛋白的适应性进行适应。最后，我们将探索可能中和潜在的HIV-1菌株的单克隆抗体和免疫粘附素可用于矢量中的免疫预防和/或治疗以对抗SIVCPZ感染（AIM＃3）。这些目标的执行不仅将独特补充HIV-1中正在进行的发病机理，预防和治愈研究，而且还将为可行性研究奠定基础，旨在翻译针对HIV-1感染的人类开发的干预措施，以使SIVCPZ感染的Chimpanze受益。