Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing.
Retroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic det...
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Main Authors: | , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
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Public Library of Science (PLoS)
2025-01-01
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Series: | PLoS Pathogens |
Online Access: | https://doi.org/10.1371/journal.ppat.1012206 |
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author | Tiana M Scott Lydia M Arnold Jordan A Powers Delaney A McCann Ana B Rowe Devin E Christensen Miguel J Pereira Wen Zhou Rachel M Torrez Janet H Iwasa Philip J Kranzusch Wesley I Sundquist Jarrod S Johnson |
author_facet | Tiana M Scott Lydia M Arnold Jordan A Powers Delaney A McCann Ana B Rowe Devin E Christensen Miguel J Pereira Wen Zhou Rachel M Torrez Janet H Iwasa Philip J Kranzusch Wesley I Sundquist Jarrod S Johnson |
author_sort | Tiana M Scott |
collection | DOAJ |
description | Retroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic detail, we reconstituted reverse transcription, genome release, and innate immune sensing of HIV-1 in a cell-free system. We found that wild-type HIV-1 capsids protect viral genomes from cGAS even after completing reverse transcription. Viral DNA could be "deprotected" by thermal stress, capsid mutations, or reduced concentrations of inositol hexakisphosphate (IP6) that destabilize the capsid. Strikingly, the capsid inhibitor lenacapavir also disrupted viral cores and dramatically potentiated cGAS activity, both in vitro and in cellular infections. Our results provide biochemical evidence that the HIV-1 capsid lattice conceals the genome from cGAS and that chemical or physical disruption of the viral core can expose HIV-1 DNA and activate innate immune signaling. |
format | Article |
id | doaj-art-c811ffd678534a8faf184f3728177641 |
institution | Kabale University |
issn | 1553-7366 1553-7374 |
language | English |
publishDate | 2025-01-01 |
publisher | Public Library of Science (PLoS) |
record_format | Article |
series | PLoS Pathogens |
spelling | doaj-art-c811ffd678534a8faf184f37281776412025-02-12T05:30:40ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-01-01211e101220610.1371/journal.ppat.1012206Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing.Tiana M ScottLydia M ArnoldJordan A PowersDelaney A McCannAna B RoweDevin E ChristensenMiguel J PereiraWen ZhouRachel M TorrezJanet H IwasaPhilip J KranzuschWesley I SundquistJarrod S JohnsonRetroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic detail, we reconstituted reverse transcription, genome release, and innate immune sensing of HIV-1 in a cell-free system. We found that wild-type HIV-1 capsids protect viral genomes from cGAS even after completing reverse transcription. Viral DNA could be "deprotected" by thermal stress, capsid mutations, or reduced concentrations of inositol hexakisphosphate (IP6) that destabilize the capsid. Strikingly, the capsid inhibitor lenacapavir also disrupted viral cores and dramatically potentiated cGAS activity, both in vitro and in cellular infections. Our results provide biochemical evidence that the HIV-1 capsid lattice conceals the genome from cGAS and that chemical or physical disruption of the viral core can expose HIV-1 DNA and activate innate immune signaling.https://doi.org/10.1371/journal.ppat.1012206 |
spellingShingle | Tiana M Scott Lydia M Arnold Jordan A Powers Delaney A McCann Ana B Rowe Devin E Christensen Miguel J Pereira Wen Zhou Rachel M Torrez Janet H Iwasa Philip J Kranzusch Wesley I Sundquist Jarrod S Johnson Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing. PLoS Pathogens |
title | Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing. |
title_full | Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing. |
title_fullStr | Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing. |
title_full_unstemmed | Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing. |
title_short | Cell-free assays reveal that the HIV-1 capsid protects reverse transcripts from cGAS immune sensing. |
title_sort | cell free assays reveal that the hiv 1 capsid protects reverse transcripts from cgas immune sensing |
url | https://doi.org/10.1371/journal.ppat.1012206 |
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