The discovery of the antiviral APOBEC3 (A3) proteins is regarded as one of the most therapeutically promising breakthroughs in HIV/AIDS molecular virology. Four different 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. In the next phase of this ongoing project, we will focus on addressing two related questions, which are regarded as major ?black boxes? in the field. Namely, how are the HIV-1 restrictive A3s regulated post-translationally, and how do these regulatory mechanisms effect the RNA-mediated process of encapsidation, which is an essential step in the overall virus restriction mechanism? These questions will be answered by combining comprehensive proteomics, genetics, and next- generation sequencing datasets to identify specific and shared A3 regulatory factors. A combination of genetics, cell biology, virology, biochemistry, and bioinformatics approaches will be used to delineate underlying molecular mechanisms. These studies are anticipated to lead to novel strategies to therapeutically boost the anti-HIV-1 activities of these enzymes and potentially contribute to a longer-term virus eradication plan.

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 molecular mechanisms regulating 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 #
4R37AI064046-15
Application #
9739877
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mcdonald, David Joseph
Project Start
2004-12-01
Project End
2024-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
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
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
Olson, Margaret E; Harris, Reuben S; Harki, Daniel A (2018) APOBEC Enzymes as Targets for Virus and Cancer Therapy. Cell Chem Biol 25:36-49
Aird, Eric J; Lovendahl, Klaus N; St Martin, Amber et al. (2018) Increasing Cas9-mediated homology-directed repair efficiency through covalent tethering of DNA repair template. Commun Biol 1:54
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
Venkatesan, S; Rosenthal, R; Kanu, N et al. (2018) Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution. Ann Oncol 29:563-572

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