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 i nclude: 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.

Public Health Relevance

HIV/AIDS ranks as one of the most important infectious diseases to have emerged in recent history. This application will define the molecular ecology and natural infection history of SIVcpz, the simian precursor of HIV-1. Elucidation of the determinants of SIV pathogenicity (or lack thereof) in natural and non-natural hosts is a high priority area in current AIDS research, since therapeutic and vaccine strategies consider amelioration of disease and prevention a desired outcome. SIVcpz infection of wild-living chimpanzees represents a critical piece in this puzzle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058715-10
Application #
8311806
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2004-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$645,300
Indirect Cost
$157,819
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Markham, A Catherine; Santymire, Rachel M; Lonsdorf, Elizabeth V et al. (2014) Rank effects on social stress in lactating chimpanzees. Anim Behav 87:195-202
Liu, Weimin; Li, Yingying; Shaw, Katharina S et al. (2014) African origin of the malaria parasite Plasmodium vivax. Nat Commun 5:3346
Wilson, Michael L; Boesch, Christophe; Fruth, Barbara et al. (2014) Lethal aggression in Pan is better explained by adaptive strategies than human impacts. Nature 513:414-7
Reed, Patricia E; Mulangu, Sabue; Cameron, Kenneth N et al. (2014) A new approach for monitoring ebolavirus in wild great apes. PLoS Negl Trop Dis 8:e3143
Stanton, Margaret A; Lonsdorf, Elizabeth V; Pusey, Anne E et al. (2014) Maternal Behavior by Birth Order in Wild Chimpanzees (Pan troglodytes): Increased Investment by First-Time Mothers. Curr Anthropol 55:483-489
Lonsdorf, Elizabeth; Travis, Dominic; Ssuna, Richard et al. (2014) Field immobilization for treatment of an unknown illness in a wild chimpanzee (Pan troglodytes schweinfurthii) at Gombe National Park, Tanzania: findings, challenges, and lessons learned. Primates 55:89-99
Gilby, Ian C; Brent, Lauren J N; Wroblewski, Emily E et al. (2013) FITNESS BENEFITS OF COALITIONARY AGGRESSION IN MALE CHIMPANZEES. Behav Ecol Sociobiol 67:373-381
Moeller, Andrew H; Shilts, Meghan; Li, Yingying et al. (2013) SIV-induced instability of the chimpanzee gut microbiome. Cell Host Microbe 14:340-5
Piel, Alex K; Stewart, Fiona A; Pintea, Lilian et al. (2013) The malagarasi river does not form an absolute barrier to chimpanzee movement in Western Tanzania. PLoS One 8:e58965
Moeller, Andrew H; Peeters, Martine; Ndjango, Jean-Basco et al. (2013) Sympatric chimpanzees and gorillas harbor convergent gut microbial communities. Genome Res 23:1715-20

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