Abstract
Most mammalian cells prevent viral infection and proliferation by expressing various restriction factors and sensors that activate the immune system. Several host restriction factors that inhibit human immunodeficiency virus type 1 (HIV-1) have been identified, but most of them are antagonized by viral proteins. Here, we describe CCHC-type zinc-finger-containing protein 3 (ZCCHC3) as a novel HIV-1 restriction factor that suppresses the production of HIV-1 and other retroviruses, but does not appear to be directly antagonized by viral proteins. It acts by binding to Gag nucleocapsid (GagNC) via zinc-finger motifs, which inhibits viral genome recruitment and results in genome-deficient virion production. ZCCHC3 also binds to the long terminal repeat on the viral genome via the middle-folded domain, sequestering the viral genome to P-bodies, which leads to decreased viral replication and production. This distinct, dual-acting antiviral mechanism makes upregulation of ZCCHC3 a novel potential therapeutic strategy.
| Original language | English (US) |
|---|---|
| Article number | 109107 |
| Journal | iScience |
| Volume | 27 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 15 2024 |
Funding
The following reagents were obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: Anti-Human Immunodeficiency Virus 1 (HIV-1) p24 Monoclonal (183-H12-5C), ARP-3537, contributed by Dr. Bruce Chesebro and Kathy Wehrly; Human Immunodeficiency Virus Type 1 (HIV-1) NL4-3 IRES-eGFP Infectious Molecular Clone (pBR43IeG-nef+), ARP-11349, contributed by Dr. Jan M\u00FCnch, Dr. Michael Schindler and Dr. Frank Kirchhoff. psPAX2-IN/HiBiT and pWPI-Luc2 plasmids were kind gifts from Dr. Kenzo Tokunaga. pMSMnG plasmid was a kind gift from Dr. Jun-ichi Sakuragi. This research was supported by Japan Agency for Medical Research and Development under grants JP22fk0410033 (to A.S.), JP21fk0108465 (to A.S.), JP22jk0210039 (to A.S.), JP22wm0325009 (to A.S. and S.H.Y.), JP22fk0410047 (to A.S. and S.H.Y.), JP23fk0410056 (to A.S.), and JP23fk0410058 (to A.S.); JSPS Grants-in-Aid for Scientific Research on Innovative Areas ( 19H04830 to S.H.Y.), JSPS Grant-in-Aid for Scientific Research (A) ( 23H00369 to S.H.Y.), JSPS Grant-in-Aid for Scientific Research (B) ( 22H02500 to A.S.), and JSPS Fund for the Promotion of Joint International Research (International Leading Research) ( JP23K20041 to A.S.); The Ito Foundation Research Grant R4 KEN132 (to A.S.); Grant for Joint Research Projects of the Research Institute for Microbial Diseases , Osaka University (to A.S.); the Joint Usage and Joint Research Programs , Institute of Advanced Medical Sciences , Tokushima University (to H.K. and S.H.Y.); Joint Research of the Exploratory Research Center on Life and Living Systems (ExCELLS) . ( 23EXC601-4 to S.H.Y.); the International Joint Research Project of the Institute of Medical Science , the University of Tokyo (to A.S.); NIH/ NIAID funding for the HIV Accessory & Regulatory Complexes (HARC) Center ( U54 AI170792 to J.F.H.), NIH/ NIAID funding for the Third Coast Center for AIDS Research ( P30 AI117943 to J.F.H.), and NIH/ NIAID funding for HIV research ( R01AI176599 , R01AI167778 , R01AI150455 , R01AI165236 , R01AI150998 , R21 AI174864 , and R56AI174877 to J.F.H.). We thank S. Dodo, Y. Shibatani, T. Nishiuchi, M. Kumeta, Y. Yu, and A. Jimpo for technical assistance. The following reagents were obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: Anti-Human Immunodeficiency Virus 1 (HIV-1) p24 Monoclonal (183-H12-5C), ARP-3537, contributed by Dr. Bruce Chesebro and Kathy Wehrly; Human Immunodeficiency Virus Type 1 (HIV-1) NL4-3 IRES-eGFP Infectious Molecular Clone (pBR43IeG-nef+), ARP-11349, contributed by Dr. Jan M\u00FCnch, Dr. Michael Schindler and Dr. Frank Kirchhoff. psPAX2-IN/HiBiT and pWPI-Luc2 plasmids were kind gifts from Dr. Kenzo Tokunaga. pMSMnG plasmid was a kind gift from Dr. Jun-ichi Sakuragi. This research was supported by Japan Agency for Medical Research and Development under grants JP22fk0410033 (to A.S.), JP21fk0108465 (to A.S.), JP22jk0210039 (to A.S.), JP22wm0325009 (to A.S. and S.H.Y.), JP22fk0410047 (to A.S. and S.H.Y.), JP23fk0410056 (to A.S.), and JP23fk0410058 (to A.S.); JSPS Grants-in-Aid for Scientific Research on Innovative Areas (19H04830 to S.H.Y.), JSPS Grant-in-Aid for Scientific Research (A) (23H00369 to S.H.Y.), JSPS Grant-in-Aid for Scientific Research (B) (22H02500 to A.S.), and JSPS Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041 to A.S.); The Ito Foundation Research Grant R4 KEN132 (to A.S.); Grant for Joint Research Projects of the Research Institute for Microbial Diseases, Osaka University (to A.S.); the Joint Usage and Joint Research Programs, Institute of Advanced Medical Sciences, Tokushima University (to H.K. and S.H.Y.); Joint Research of the Exploratory Research Center on Life and Living Systems (ExCELLS). (23EXC601-4 to S.H.Y.); the International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to A.S.); NIH/NIAID funding for the HIV Accessory & Regulatory Complexes (HARC) Center (U54 AI170792 to J.F.H.), NIH/NIAID funding for the Third Coast Center for AIDS Research (P30 AI117943 to J.F.H.), and NIH/NIAID funding for HIV research (R01AI176599, R01AI167778, R01AI150455, R01AI165236, R01AI150998, R21 AI174864, and R56AI174877 to J.F.H.). We thank S. Dodo, Y. Shibatani, T. Nishiuchi, M. Kumeta, Y. Yu, and A. Jimpo for technical assistance. Experiments were designed by B.Y. D.C. J.L.-S. P.S. J.F.H. A.S. and S.H.Y. Plasmids construction, recombinant protein purification, protein pull-down assay, RNA pull-down assay, EMSA, RNA preparation, reverse transcription quantitative PCR, and stable cell generation were performed by B.Y. and Y.L.T. Cell culture and transfection, confocal fluorescence microscopy, flow cytometry was performed by B.Y. Y.L.T. E.P.B. S.H.Y. and A.S. BioID assay was performed by B.Y. and H.K. ZCCHC3 knockout cells generation and HiBiT assay were performed by Y.L.T. and A.S. Primary cell experiments were conducted by D.C. Data analysis was completed by B.Y. S.H.Y. and A.S. Manuscript writing, figure design, and editing was done by B.Y. D.C. H.K. J.F.H. A.S. and S.H.Y. J.F.H. A.S. and S.H.Y. supervised and funded the project. J.F.H. has received research support, paid to Northwestern University, from Gilead Sciences and is a paid consultant for Merck.
Keywords
- Biological sciences
- Immunology
- Virology
ASJC Scopus subject areas
- General
