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（由申请人提供）： 黑猩猩猿免疫缺陷病毒 (SIVcpz) 是人类免疫缺陷病毒 1 型 (HIV-1) 的前体，而 1 型人类免疫缺陷病毒是艾滋病大流行的原因 (1-3)。在过去的十年中，我们的小组研究了野生黑猩猩的 SIVcpz 感染，将非侵入性病毒检测与黑猩猩行为、生活史、生育力和死亡率的研究相结合 (1-60)。这些研究对 SIVcpz 的生物学和致病性 (4-6)、其患病率和地理分布 (7-9)、人畜共患潜力 (8、10-12) 及其对抗有效人类限制因素的能力 (12-19) 提供了前所未有的见解。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，并在其粪便样本中发现了新病毒 (43-45)、寄生虫 (46-50) 和微生物群 (51-56)，包括其他主要人类病原体的前体 (46、47、57)。这项工作大部分是在贡贝国家公园进行的，这是世界上唯一可以在习惯的黑猩猩身上近距离研究 SIVcpz 感染的现场地点。在此应用中，我们建议利用这些发现（其中许多现在才取得成果），并继续对感染 SIVcpz 的野生猿进行非侵入性调查，以帮助它们生存并增强人类健康。我们的工作假设是，对自然黑猩猩宿主中人类艾滋病病毒前体的研究将继续揭示对 HIV/SIV 发病机制的重要新见解，并导致新的干预措施，使人类和黑猩猩都受益。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的病理学及其对三个黑猩猩群落的影响，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勒生态系统 (GME)，该系统是约 2,500 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猿类病毒跨越物种屏障到达人类时都需要对 Gag 蛋白进行适应，并阐明病毒基质蛋白 (Gag-30) 30 位的一个特定氨基酸残基如何增加人类 CD4+ T 细胞中 SIVcpz 对 1 型干扰素 (IFN) 的抵抗力（目标#2）。最后，我们将探讨有效中和多种 HIV-1 毒株的单克隆抗体和免疫粘附素是否可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 发病机制、预防和治疗研究，还将为旨在将针对 HIV-1 感染人类开发的干预措施转化为使 SIVcpz 感染黑猩猩受益的可行性研究奠定基础。