Abstract
We have previously described polyglutamine-binding protein 1 (PQBP1) as an adapter required for the cyclic GMP-AMP synthase (cGAS)-mediated innate response to the human immunodeficiency virus 1 (HIV-1) and other lentiviruses. Cytoplasmic HIV-1 DNA is a transient and low-abundance pathogen-associated molecular pattern (PAMP), and the mechanism for its detection and verification is not fully understood. Here, we show a two-factor authentication strategy by the innate surveillance machinery to selectively respond to the low concentration of HIV-1 DNA, while distinguishing these species from extranuclear DNA molecules. We find that, upon HIV-1 infection, PQBP1 decorates the intact viral capsid, and this serves as a primary verification step for the viral nucleic acid cargo. As reverse transcription and capsid disassembly initiate, cGAS is recruited to the capsid in a PQBP1-dependent manner. This positions cGAS at the site of PAMP generation and sanctions its response to a low-abundance DNA PAMP.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2871-2884.e6 |
| Journal | Molecular cell |
| Volume | 82 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 4 2022 |
Funding
The authors would like to thank Zeli Zhang for reagent preparations; SBP Flow Cytometry core for technical assistance; and Tanya Dragic for manuscript editing. Research reported in this publication was supported by NIAID of the National Institutes of Health under award numbers (R01 AI127302-01A1, R01AI162260, P50AI150481, P50AI150464, P50 AI150476, P30 AI117943, R01 AI150455, R01 AI165236, R01AI150998, R01 AI105184-02 Supplement, K22AI140963, and AI150464) and cFAR Development Grant and CHRP Basic Bio Pilot BB19-SBMR-0, Gilead Sciences Research Scholars Program in HIV and by the German Research Foundation (Deutsche Forschungsgemeinschaft-DFG; SPP1923 project KO4573/1-2). 90%/$500,000 of the total project costs were financed with federal funding (USA). 10%/$55,000 of the total costs were financed with non-federal and non-USA fundings. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conceptualization, S.M.Y. J.I.M. and S.K.C.; methodology, S.M.Y. J.I.M. A.T. and D.L.; validation, A.T.; formal analysis, G.C.C. L.R. and J.I.M.; investigation, S.M.Y. J.I.M. D.L. A.T. N.A. M.T.S.-A. J.T. and N.V.F.; resources, H.C. L.M.S. S.G. J.F.H.; writing – original draft, S.M.Y. J.I.M. D.L. and T.B.; writing – review & editing, S.M.Y. S.K.C. A.G.-S. T.J.H. Y.X. and R.K.; visualization, S.M.Y. J.I.M. and T.B.; supervision, S.K.C. T.J.H. and A.G.-S.; project administration, S.M.Y.; funding acquisition, S.K.C. A.G.-S. and S.M.Y. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen, and Pfizer, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Sequirus, Janssen, and Astrazeneca outside of the reported work. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. The S.K.C. laboratory has received research support from Eli Lilly & Co. Boehringer Ingelheim, Merck & Co. Cidara Therapeutics, outside of the reported work. S.K.C. has consulting agreements for the following companies involving cash and/or stock: Pagoda Genomics, Cidara Therapeutics, and Samsara Biocapital, outside of the reported work. S.K.C. is inventor on patents and patent applications on the use of antivirals, adjuvants, and immunotherapies for the treatment and prevention of virus infections and cancer, owned by Sanford Burnham Prebys Medical Discovery Institute and Scripps Research, outside of the reported work. The authors would like to thank Zeli Zhang for reagent preparations; SBP Flow Cytometry core for technical assistance; and Tanya Dragic for manuscript editing. Research reported in this publication was supported by NIAID of the National Institutes of Health under award numbers ( R01 AI127302-01A1 , R01AI162260 , P50AI150481 , P50AI150464 , P50 AI150476 , P30 AI117943 , R01 AI150455 , R01 AI165236 , R01AI150998 , R01 AI105184-02 Supplement, K22AI140963 , and AI150464 ) and cFAR Development Grant and CHRP Basic Bio Pilot BB19-SBMR-0 , Gilead Sciences Research Scholars Program in HIV and by the German Research Foundation (Deutsche Forschungsgemeinschaft- DFG ; SPP1923 project KO4573/1-2 ). 90%/$500,000 of the total project costs were financed with federal funding (USA). 10%/$55,000 of the total costs were financed with non-federal and non-USA fundings. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health .
Keywords
- HIV-1 capsid
- PQBP1
- cGAS
- innate sensing
- two-factor authentication
- uncoating
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
