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: 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
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2025-01-01
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.
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institution Kabale University
issn 1553-7366
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language English
publishDate 2025-01-01
publisher Public Library of Science (PLoS)
record_format Article
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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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