Abstract
The cytoplasmic human Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) cytidine deaminases G and F (A3G and A3F) can block the spread of human immunodeficiency virus (HIV). HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor (Vif). Vif causes proteasomal degradation of A3G and A3F proteins (A3G/F) in HIV-producing cells to ensure infectivity of virions subsequently released from these cells. Here, we optimized a lead compound reported previously to boost cellular levels of A3G. The modified analogs designed, synthesized, and evaluated here inhibit cell-mediated post-translational degradation of A3G/F, whether Vif is present or not. This increases A3G/F incorporation into Vif-positive virions to decrease viral infectivity. The compounds and processes described here can facilitate the development of new anti-HIV therapeutics whose host-targeted effect may not be evaded by resistance-conferring mutations in HIV Vif.
| Original language | English (US) |
|---|---|
| Article number | 514 |
| Journal | Viruses |
| Volume | 17 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2025 |
Funding
We acknowledge NU\u2019s Medicinal and Synthetic Chemistry Core, formerly led by G.E.S. (partially supported by P30 CA 060553, as well as NU, the Chicago Biomedical Consortium, and the Searle Funds at The Chicago Community Trust); the core resources (including HIV p24 assays) and collaborative infrastructure of the Third Coast Center for AIDS Research (P30 AI 117943); NU Feinberg School of Medicine Department of Medicine\u2019s Division of Infectious Diseases; and collaborations (not described and only cited here) with Mangala Rao (Walter Reed Army Institute of Research and the US Military HIV Research Program), Sofia Casares (US Military Malaria Vaccine Development, Naval Medical Research Center, and Walter Reed Army Institute of Research), and their laboratory colleagues. The expert assistance of the NU Innovation and New Ventures Office on patent application submission is also appreciated. We also acknowledge reagents provided by the NIH HIV Reagent Program (now part of BEI Resources Repository), including TZM-bl cells deposited by John C. Kappes, Xiaoyun Wu, and Tranzyme, Inc.; anti-APOBEC3F(C18) polyclonal antibody from Michael Malim; anti-APOBEC3G polyclonal antibody from Klaus Strebel and Sandra Kao; and an anti-Vif polyclonal antibody from Bryan Cullen. We also acknowledge the Tennessee Center for AIDS Research Virology Core for anti-p24 monoclonal antibody 183-H12\u20135C. This work was supported, in part, by the following awards from the National Institutes of Health (NIH): P01 AI 131346 (awarded to R.T.D. and C.S.); a pilot award from P30 AI 117943 (awarded to C.S.); voucher funding from UM1TR005121 (awarded to C.S.); administrative supplements to P30 CA 060553 (awarded to Leon Platanias); T32 GM008061 (supporting A.M.S); T32 AI007476 (supporting C.C.V.). Other support is appreciated from the American Foundation for AIDS Research (amfAR, awarded to R.T.D.). Generous support for foundational research enabling this subsequent work is acknowledged from the Bristol Myers Squibb Unrestricted Biomedical Research Grants Program (awarded to R.T.D.). The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health or any other funder.
Keywords
- APOBEC3F
- APOBEC3G
- HIV
- HIV cure research
- HIV infectivity
- HIV-1
- Vif
ASJC Scopus subject areas
- Infectious Diseases
- Virology
