Treating and preventing infectious disease requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. Traditionally, this amounted to a focus on genes of the adaptive immune system. However, equally important are those cellular factors that interact directly with viral macromolecules, either as positive cofactors for virus replication, or as intrinsic host mechanisms for suppressing viral infection. The latter includes the restriction factors - with TRIM5, APOBEC3, BST2/tetherin, SAMHD1, Schlafen-11 and Mx2 being well-studied examples. While individual restriction factors have been extensively studied in isolation (typicall by overexpression in heterologous cell lines), their combined impact at the level of the host organism and the host-population has not been carefully examined. While the antiviral activity of these restriction factors in cell culture is consistent with a role in preventing cross-species transmission of primate lentiviruses in nature, there are little-to-no data that directly support tis hypothesis. In this proposal, we will track the evolution of primate lentiviruses during the earliet stages of adapting to a non-native host (SIVsmm in rhesus macaques) using a combination of next- generation sequencing and bioinformatics tools customized for studying RNA virus populations (AIMS 1 & 3); and establish the biological significance of individual restrictions in terms of the evolutionary consequences of resistance for relative viral fitness (AIM 2).

Public Health Relevance

This study will determine the extent to which host genes act as genetic barriers to cross-species transmission of primate lentiviruses, and how these AIDS-causing viruses evolve to overcome such barriers when they spillover from their natural reservoirs into non-native hosts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI083118-07A1
Application #
8993274
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Stansell, Elizabeth H
Project Start
2009-07-21
Project End
2020-05-31
Budget Start
2015-06-15
Budget End
2016-05-31
Support Year
7
Fiscal Year
2015
Total Cost
$382,775
Indirect Cost
$132,775
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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