Understanding, managing and treating infectious disease in the long-term requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. This includes genes of the adaptive immune system, but equally important are those factors that interact directly with viral macromolecules either as positive cofactors for replication or as intrinsic host mechanisms for evading or attenuating infection. Variability in susceptibility to infection, disease course and pathogenesis is due in large part to the combined effects of genetic variation at multiple loci. The TRIM5alpha protein functions as an intrinsic inhibitor of retroviral replication, and the primate TRIM5 locus displays an unusually high degree of interspecies divergence, consistent with an evolutionary history of strong positive selection. We have discovered that extensive within-species variation, or polymorphism, exists in the TRIM5alpha coding sequences of two geographically distinct species of old world monkeys of particular relevance to HIV/AIDS research, rhesus macaques and sooty mangabeys.
The specific aims of this proposal are unified by the goal of exploiting the extensive, naturally occurring adaptive variations in nonhuman primates to gain insight into the structure and function of TRIM5alpha, and to determine the extent of TRIM5alpha's influence on viral replication and disease progression in vivo.

Public Health Relevance

These investigations will improve our understanding of how host genetic variation impacts viral infection, provide specific insight into mechanisms of TRIM51 mediated restriction, and lead to improved use of experimental models for HIV/AIDS. Moreover, the results will provide insight into the development of novel inhibitors of the post-entry stage of HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083118-05
Application #
8291198
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sanders, Brigitte E
Project Start
2009-07-21
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$383,464
Indirect Cost
$138,439
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
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McCarthy, Kevin R; Johnson, Welkin E (2014) Plastic proteins and monkey blocks: how lentiviruses evolved to replicate in the presence of primate restriction factors. PLoS Pathog 10:e1004017
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Wu, Fan; Kirmaier, Andrea; Goeken, Robert et al. (2013) TRIM5 alpha drives SIVsmm evolution in rhesus macaques. PLoS Pathog 9:e1003577
McCarthy, Kevin R; Schmidt, Aaron G; Kirmaier, Andrea et al. (2013) Gain-of-sensitivity mutations in a Trim5-resistant primary isolate of pathogenic SIV identify two independent conserved determinants of Trim5? specificity. PLoS Pathog 9:e1003352
Byrareddy, Siddappa N; Ayash-Rashkovsky, Mila; Kramer, Victor G et al. (2013) Live attenuated Rev-independent NefýýSIV enhances acquisition of heterologous SIVsmE660 in acutely vaccinated rhesus macaques. PLoS One 8:e75556
Patel, Vainav; Jalah, Rashmi; Kulkarni, Viraj et al. (2013) DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge. Proc Natl Acad Sci U S A 110:2975-80
Henzy, Jamie E; Johnson, Welkin E (2013) Pushing the endogenous envelope. Philos Trans R Soc Lond B Biol Sci 368:20120506
Krupp, Annabel; McCarthy, Kevin R; Ooms, Marcel et al. (2013) APOBEC3G polymorphism as a selective barrier to cross-species transmission and emergence of pathogenic SIV and AIDS in a primate host. PLoS Pathog 9:e1003641
Diehl, William E; Johnson, Welkin E; Hunter, Eric (2013) Elevated rate of fixation of endogenous retroviral elements in Haplorhini TRIM5 and TRIM22 genomic sequences: impact on transcriptional regulation. PLoS One 8:e58532

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