The discovery of the antiviral APOBEC3 (A3) proteins is regarded as one of the most therapeutically promising breakthroughs in HIV/AIDS molecular virology in the last decade. Several A3 proteins have the capacity to restrict HIV replication by incorporating into assembling viral particles, physically interfering with the progression of reverse transcription, and deaminating viral cDNA cytosines to uracils. The latter antiviral activity is the defining hallmark of A3-mediated restriction, explaining the genomic strand G-to-A mutations that are frequently observed in patient-derived viral sequences. Here, we will address two major questions. First, we will ask whether stable A3H haplotypes provide a barrier to HIV acquisition in instances where the transmitting virus originates from a person with an unstable A3H haplotype. Moreover, in individuals where the virus overcomes this barrier and transmission still occurs, we also ask how the virus adapts to efficiently counteract stable A3H and how this relates to disease progression. These experiments are motivated by preliminary data showing that stable A3H haplotypes potently restrict the replication of viruses with naturally occurring hypofunctional vif alleles. These studies have the potential to explain why some highly exposed individuals naturally resist viral infection. Second, we will ask whether HIV has additional mechanisms, independent of Vif, to counteract restriction by A3 proteins. This will be addressed through a series of vif-null virus adaptation experiments to restrictive pressures imposed by A3 proteins, followed by comprehensive analyses of the resulting mutations to deduce the underlying escape mechanisms. These experiments are anticipated to provide genetic portals into aspects of the restriction mechanism that are poorly understood such as A3 post-translational regulation, assembly, packaging, and encapsidation. Together, our studies on transmission could have immediate clinical implications, and our studies on Vif-independent resistance will provide novel mechanistic insights and have longer-term clinical implications as the field moves further toward the development of therapeutics such as Vif inhibitors that will be able to leverage this powerful innate immune defense system to block HIV replication and pathogenesis.

Public Health Relevance

HIV/AIDS is still a pandemic problem. Targeted innate immune therapies have yet to be developed against this virus. Fundamental research on the antiviral APOBEC3 enzymes will stimulate the development of innovative HIV/AIDS therapeutics that work by leveraging this innate immune defense system to extinguish virus replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI064046-13
Application #
9397503
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Mcdonald, David Joseph
Project Start
2005-07-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
13
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
Shaban, Nadine M; Shi, Ke; Lauer, Kate V et al. (2018) The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism. Mol Cell 69:75-86.e9
Salamango, Daniel J; Becker, Jordan T; McCann, Jennifer L et al. (2018) APOBEC3H Subcellular Localization Determinants Define Zipcode for Targeting HIV-1 for Restriction. Mol Cell Biol 38:
Salamango, Daniel J; McCann, Jennifer L; Demir, Özlem et al. (2018) APOBEC3B Nuclear Localization Requires Two Distinct N-Terminal Domain Surfaces. J Mol Biol 430:2695-2708
Wang, Jiayi; Shaban, Nadine M; Land, Allison M et al. (2018) Simian Immunodeficiency Virus Vif and Human APOBEC3B Interactions Resemble Those between HIV-1 Vif and Human APOBEC3G. J Virol 92:
Hayward, Joshua A; Tachedjian, Mary; Cui, Jie et al. (2018) Differential Evolution of Antiretroviral Restriction Factors in Pteropid Bats as Revealed by APOBEC3 Gene Complexity. Mol Biol Evol 35:1626-1637
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St Martin, Amber; Salamango, Daniel; Serebrenik, Artur et al. (2018) A fluorescent reporter for quantification and enrichment of DNA editing by APOBEC-Cas9 or cleavage by Cas9 in living cells. Nucleic Acids Res 46:e84
Ikeda, Terumasa; Symeonides, Menelaos; Albin, John S et al. (2018) HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G. PLoS Pathog 14:e1007010
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
Tennyson, Rachel L; Walker, Susanne N; Ikeda, Terumasa et al. (2018) Evaluation of sequence variability in HIV-1 gp41 C-peptide helix-grafted proteins. Bioorg Med Chem 26:1220-1224

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