The human immunodeficiency virus (HIV) is opposed by host cell factors, called ?restriction factors? with the potential to significantly control viral replication and affect disease progression and viral transmission. Our hypothesis is that the critical balance between the activity of restriction factors and the ability of the virus to antagonize or evade these factors plays in important role in HIV evolution, and ultimately, our ability to cure this infection. 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, and a newly discovered polymorphism in APOBEC3C has increased activity in a subset of humans. Antagonism of all of the APOBEC3 proteins is dependent on the activity of the HIV-1 Vif protein which itself is polymorphic and must attack multiple host proteins at once. We will continue our studies on the interactions of restriction factors against HIV by determining the consequences of virus going from individuals with differing repertoires of APOBEC3 proteins. We will use an already established discordant couples cohort to understand the evolution and function of Vif proteins when virus is transmitted from an individual with one APOBEC3H genotype to a person with a different APOBEC3H genotype. In parallel, we will also 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. In addition, we will determine the importance and mechanism of a gain-of-function polymorphism in APOBEC3C. We will further study the evolutional potential of Vif-APOBEC3 interactions by determining the steps needed for SIV Vif proteins to adapt to antagonize the human APOBEC3 repertoire. Finally, we have initiated an innovative and flexible CRISPR/Cas9 screen for novel restriction factors that will provide further insights into the interactions between HIV and its host that affect virus replication. Overall, the goal of this proposal is to understand how the 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 30 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 and evolves around our defenses, and how human defense genes against HIV might be used to control this virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030927-27
Application #
9460998
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Mcdonald, David Joseph
Project Start
1991-08-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
27
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Wittkopp, Cristina J; Adolph, Madison B; Wu, Lily I et al. (2016) A Single Nucleotide Polymorphism in Human APOBEC3C Enhances Restriction of Lentiviruses. PLoS Pathog 12:e1005865
McLaughlin Jr, Richard N; Gable, Jacob T; Wittkopp, Cristina J et al. (2016) Conservation and Innovation of APOBEC3A Restriction Functions during Primate Evolution. Mol Biol Evol 33:1889-901
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

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