MOLECULAR DETERMINANTS OF HIV HYPERMUTATION ABSTRACT Four human APOBEC3 enzymes have the potential to inhibit HIV-1 infection by inducing G-to-A mutations, and these mutations occur in two different dinucleotide contexts: GG-to-AG (APOBEC3G) or GA-to-AA (APOBEC3D, APOBEC3F, and APOBEC3H). Unexpectedly, only one or the other of these hypermutation signatures is predominant in most HIV-1 sequences from infected patients. This biased mutation distribution implies the existence of a mechanism that prevents APOBEC3 enzymes from targeting HIV-1 simultaneously. We hypothesize that this biased mutation distribution is due to natural variations in the APOBEC3G and APOBEC3H genes and that particular alleles define stronger or weaker antiviral responses against HIV-1. In support of this idea, we have identified genetically linked APOBEC3G and APOBEC3H alleles that undergo differential splicing in different human populations. These data and viral hypermutation analyses indicate that in most patients either APOBEC3G or APOBEC3H haplotype II (but not both enzymes at the same time) has the capability to hypermutate HIV-1. Here, we will further test this hypothesis using a combination of computational and molecular virology approaches. Our studies have the potential to reveal natural strengths and weakness in the human innate immune response and discover the underlying molecular mechanisms.

Public Health Relevance

MOLECULAR DETERMINANTS OF HIV HYPERMUTATION RELEVANCE Our proposal seeks to explain G-to-A mutation biases observed in clinical HIV-1 sequences. These studies have the potential to reveal strengths and weaknesses in the APOBEC-mediated innate immune response to HIV-1 infection and uncover different strategies that HIV-1 uses to counteract APOBEC enzymes in different human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI138793-01A1
Application #
9620876
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Kuo, Lillian S
Project Start
2018-05-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ebrahimi, Diako; Richards, Christopher M; Carpenter, Michael A et al. (2018) Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease. Nat Commun 9:4137