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.

Public Health Relevance

Effective approaches are urgently needed to prevent and cure HIV-1 infection. SIVcpz, the precursor of pandemic HIV-1, causes immunodeficiency and AIDS in chimpanzees. Studying SIVcpz infection in its natural host provides a unique opportunity to compare and contrast the mechanisms of AIDS pathogenesis in man's closest relative. This approach has already uncovered invaluable insight into the origins, evolution and pathobiology of HIV-1, and may inform new approaches to prevent and eradicate HIV-1/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI120810-03
Application #
9392520
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Lawrence, Diane M
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Walker, Kara K; Rudicell, Rebecca S; Li, Yingying et al. (2017) Chimpanzees breed with genetically dissimilar mates. R Soc Open Sci 4:160422
Barbian, Hannah J; Jackson-Jewett, Raven; Brown, Corrine S et al. (2017) Effective treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee. Retrovirology 14:35
Loy, Dorothy E; Liu, Weimin; Li, Yingying et al. (2017) Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Int J Parasitol 47:87-97
Mack, Katharina; Starz, Kathrin; Sauter, Daniel et al. (2017) Efficient Vpu-Mediated Tetherin Antagonism by an HIV-1 Group O Strain. J Virol 91:
Wroblewski, Emily E; Guethlein, Lisbeth A; Norman, Paul J et al. (2017) Bonobos Maintain Immune System Diversity with Three Functional Types of MHC-B. J Immunol 198:3480-3493
Liu, Weimin; Sherrill-Mix, Scott; Learn, Gerald H et al. (2017) Wild bonobos host geographically restricted malaria parasites including a putative new Laverania species. Nat Commun 8:1635
Moeller, Andrew H; Caro-Quintero, Alejandro; Mjungu, Deus et al. (2016) Cospeciation of gut microbiota with hominids. Science 353:380-2
Liu, Weimin; Sundararaman, Sesh A; Loy, Dorothy E et al. (2016) Multigenomic Delineation of Plasmodium Species of the Laverania Subgenus Infecting Wild-Living Chimpanzees and Gorillas. Genome Biol Evol 8:1929-39
Moeller, Andrew H; Foerster, Steffen; Wilson, Michael L et al. (2016) Social behavior shapes the chimpanzee pan-microbiome. Sci Adv 2:e1500997