As the worldwide AIDS epidemic begins its fourth decade, with ~34 million people living with HIV-AIDS around the globe, a cure or vaccine for HIV-1 still eludes us. Fortunately over 30 drugs that belong to seven classes targeting various stages in the life cycle of HIV have improved the overall quality and life expectancy of HIV-infected patients. To date, the most successful anti-viral HIV drugs abrogate functions of HIV enzymes. However, viral diversity from varied clades or poor adherence has led to the emergence of drug resistance preventing the therapeutic control of many HIV infections, warranting the identification of novel targets and therapeutic strategies. Our long-term goal is to develop new, complementary, anti-viral strategies by activating the natural anti-HIV functions of human restriction factors. The APOBEC3 (A3) family of single and double domain cytidine deaminases, particularly A3G, are critical enzymes in this restriction and whose molecular mechanisms may be leveraged in developing such host activated therapeutic strategies. We hypothesize that the molecular interactions and differential specificities of A3s to nucleic acids and HIV-1 Vif provide epitopes that once characterized will provide target sites for future therapeutic development.

Public Health Relevance

As the worldwide AIDS epidemic begins its fourth decade, with ~34 million people living with HIV-AIDS around the globe, a cure or vaccine for HIV-1 still eludes us. Although over 30 drugs targeting various stages in the life cycle of HIV have improved the overall quality and life expectancy of HIV-infected patients, viral diversity from varied clades or poor adherence has led to the emergence of drug resistance preventing the therapeutic control of many HIV infections, warranting the identification of novel targets and therapeutic strategies. Our long-term goal is to develop new, complementary, anti-viral strategies by activating the natural anti-HIV functions of human APOBEC3 (A3) family of cytidine deaminases which can mutate HIV-1 genome and restrict viral infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM118474-01
Application #
9080050
Study Section
Special Emphasis Panel (ZRG1-AARR-E (02))
Program Officer
Sakalian, Michael
Project Start
2016-09-01
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$614,226
Indirect Cost
$147,149
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Silvas, Tania V; Hou, Shurong; Myint, Wazo et al. (2018) Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions. Sci Rep 8:7511
Maiti, Atanu; Myint, Wazo; Kanai, Tapan et al. (2018) Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA. Nat Commun 9:2460
Kouno, Takahide; Silvas, Tania V; Hilbert, Brendan J et al. (2017) Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity. Nat Commun 8:15024
Prabhu, Ponnandy; Shandilya, Shivender M D; Britan-Rosich, Elena et al. (2016) Inhibition of APOBEC3G activity impedes double-stranded DNA repair. FEBS J 283:112-29