The HIV-1 pathogenic factor Nef and its interactions with host proteins are important for viral pathogenesis, but their role in HIV-1 latency is not known. Nef-associated factor 1 (Naf1), also known as A20-binding inhibitor of NF-kB (ABIN1), is a host protein that inhibits NF-kB activation. NF-kB is a well-known regulator HIV-1 gene expression and viral latency. Intriguingly, our preliminary studies suggest that Naf1 and Nef interplay regulates HIV-1 gene transcription and viral latency. We found that (1) Naf1 suppresses NF-kB- dependent HIV-1 gene expression and Nef counteracts the effects; and (2) Naf1 maintains HIV-1 latency by suppressing viral gene transcription, while Nef antagonizes the effects. Therefore, we propose to delineate the mechanisms of Nef-Naf1 interactions in regulating HIV-1 latency and to seek a new approach to overcome viral latency. Our central hypotheses are (1) Naf1 maintains HIV-1 latency by suppressing NF- kB-dependent viral gene transcription; (2) Nef antagonizes the inhibitory effects of Naf1 by inducing Naf1 phosphorylation, which activates PI3K/Akt signaling and leads to HIV-1 reactivation from latency. We propose two specific aims to test these novel hypotheses.
Aim 1. To investigate the mechanisms by which the Naf1-Nef interaction regulates HIV-1 gene expression.
Aim 2. To determine the function of Naf1 and Nef interactions in modulating HIV-1 latency in primary CD4+ T cells. Accomplishing the proposed studies through our collaborative efforts will provide novel insights into the viral and cellular mechanisms of modulating HIV-1 latency. Our expected results will provide a basis to target Nef-Naf1 interactions and to enhance anti-retroviral therapy toward a functional cure for HIV-1/AIDS.

Public Health Relevance

HIV infection is the leading killer worldwide among infectious diseases, incurring 2-3 million AIDS deaths annually. HIV-1 latency is the major barrier to cure AIDS using antiviral regimens. Our collaborative HIV/AIDS studies with researchers in China will provide important new information on the cellular and viral mechanisms that regulate HIV-1 latency. Our mechanistic research of HIV-1 latency will facilitate the development of more effective strategies to eradicate HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI120209-02
Application #
9120298
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kuo, Lillian S
Project Start
2015-08-05
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Wang, Qiankun; Chen, Shuliang; Xiao, Qiaoqiao et al. (2017) Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection. Retrovirology 14:51

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