The human immunodeficiency virus (HIV) both relies on host cell proteins for its replication, and is opposed by host cell factors, called "restriction factors" with the potential to significantly control viral replication. Our hypothesis is that humans are so susceptible to HIV because our antiviral genes are poorly adapted to this virus, and because HIV-1 has adapted to humans by its own evolution of specific antagonists to these antiviral genes. While some restriction factors are very active against HIV, others work poorly in humans or are polymorphic in the human population with both active and inactive versions. In the APOBEC3 locus of restriction factors, APOBEC3H stands out because some humans make active versions of this protein, while others do not. We will determine how important APOBEC3H is for HIV infection by determining whether or not HIV adapts in humans who encode the most active form of APOBEC3H. We will also study the evolution and function of APOBEC3DE which is a restriction factor that has rapidly evolved since the human-chimpanzee divergence, and we will the exploit the natural infection of African Green Monkeys (AGMs) subspecies with divergent SIVs to understand how polymorphism in the APOBEC3 locus affects the evolution of the lentivirus-host relationship. Finally, we will characterize a restriction factor against HIV, called Viperin, that acts at a late stage of virus replication by a novel mechanism. Overall, the goal of this proposal is to understand how the past evolution and function of these restriction factors impacts HIV replication in humans.

Public Health Relevance

The human immunodeficiency virus (HIV) is the major viral pandemic of the past 25 years. Our study will elucidate the human defenses to HIV in order to understand why humans are so susceptible to this virus, how HIV evades our defenses, and how previous infections of human ancestors may have shaped the evolution of our viral defenses to HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI030927-24S1
Application #
8915362
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Stansell, Elizabeth H
Project Start
1991-08-01
Project End
2016-06-30
Budget Start
2014-08-22
Budget End
2015-06-30
Support Year
24
Fiscal Year
2014
Total Cost
$133,957
Indirect Cost
$57,845
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Mitchell, Patrick S; Young, Janet M; Emerman, Michael et al. (2015) Evolutionary Analyses Suggest a Function of MxB Immunity Proteins Beyond Lentivirus Restriction. PLoS Pathog 11:e1005304
Matsen 4th, Frederick A; Small, Christopher T; Soliven, Khanh et al. (2014) A novel Bayesian method for detection of APOBEC3-mediated hypermutation and its application to zoonotic transmission of simian foamy viruses. PLoS Comput Biol 10:e1003493
Refsland, Eric W; Hultquist, Judd F; Luengas, Elizabeth M et al. (2014) Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity. PLoS Genet 10:e1004761
Spragg, Chelsea J; Emerman, Michael (2013) Antagonism of SAMHD1 is actively maintained in natural infections of simian immunodeficiency virus. Proc Natl Acad Sci U S A 110:21136-41
Malfavon-Borja, Ray; Wu, Lily I; Emerman, Michael et al. (2013) Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes. Proc Natl Acad Sci U S A 110:E583-92
Fregoso, Oliver I; Ahn, Jinwoo; Wang, Chuanping et al. (2013) Evolutionary toggling of Vpx/Vpr specificity results in divergent recognition of the restriction factor SAMHD1. PLoS Pathog 9:e1003496
Etienne, Lucie; Hahn, Beatrice H; Sharp, Paul M et al. (2013) Gene loss and adaptation to hominids underlie the ancient origin of HIV-1. Cell Host Microbe 14:85-92
Etienne, Lucie; Emerman, Michael (2013) The mongoose, the pheasant, the pox, and the retrovirus. PLoS Biol 11:e1001641
Compton, Alex A; Emerman, Michael (2013) Convergence and divergence in the evolution of the APOBEC3G-Vif interaction reveal ancient origins of simian immunodeficiency viruses. PLoS Pathog 9:e1003135

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