HIV-1 with gag processing defects activates cGAS sensing.
HIV-1
/ immunology
Humans
gag Gene Products, Human Immunodeficiency Virus
/ genetics
Immunity, Innate
Nucleotidyltransferases
/ genetics
Antiviral Restriction Factors
Macrophages
/ immunology
Tripartite Motif Proteins
/ genetics
Ubiquitin-Protein Ligases
/ genetics
THP-1 Cells
Carrier Proteins
/ genetics
Immune Evasion
Capsid
/ metabolism
Virus Replication
Virion
/ metabolism
Host-Pathogen Interactions
/ immunology
DNA, Viral
/ genetics
Cell Line
Capsid
DNA sensing
HIV-1
Interferon
cGAS
Journal
Retrovirology
ISSN: 1742-4690
Titre abrégé: Retrovirology
Pays: England
ID NLM: 101216893
Informations de publication
Date de publication:
23 May 2024
23 May 2024
Historique:
received:
08
04
2024
accepted:
07
05
2024
medline:
23
5
2024
pubmed:
23
5
2024
entrez:
22
5
2024
Statut:
epublish
Résumé
Detection of viruses by host pattern recognition receptors induces the expression of type I interferon (IFN) and IFN-stimulated genes (ISGs), which suppress viral replication. Numerous studies have described HIV-1 as a poor activator of innate immunity in vitro. The exact role that the viral capsid plays in this immune evasion is not fully understood. To better understand the role of the HIV-1 capsid in sensing we tested the effect of making HIV-1 by co-expressing a truncated Gag that encodes the first 107 amino acids of capsid fused with luciferase or GFP, alongside wild type Gag-pol. We found that unlike wild type HIV-1, viral particles produced with a mixture of wild type and truncated Gag fused to luciferase or GFP induced a potent IFN response in THP-1 cells and macrophages. Innate immune activation by Gag-fusion HIV-1 was dependent on reverse transcription and DNA sensor cGAS, suggesting activation of an IFN response by viral DNA. Further investigation revealed incorporation of the Gag-luciferase/GFP fusion proteins into viral particles that correlated with subtle defects in wild type Gag cleavage and a diminished capacity to saturate restriction factor TRIM5α, likely due to aberrant particle formation. We propose that expression of the Gag fusion protein disturbs the correct cleavage and maturation of wild type Gag, yielding viral particles that are unable to effectively shield viral DNA from detection by innate sensors including cGAS. These data highlight the crucial role of capsid in innate evasion and support growing literature that disruption of Gag cleavage and capsid formation induces a viral DNA- and cGAS-dependent innate immune response. Together these data demonstrate a protective role for capsid and suggest that antiviral activity of capsid-targeting antivirals may benefit from enhanced innate and adaptive immunity in vivo.
Sections du résumé
BACKGROUND
BACKGROUND
Detection of viruses by host pattern recognition receptors induces the expression of type I interferon (IFN) and IFN-stimulated genes (ISGs), which suppress viral replication. Numerous studies have described HIV-1 as a poor activator of innate immunity in vitro. The exact role that the viral capsid plays in this immune evasion is not fully understood.
RESULTS
RESULTS
To better understand the role of the HIV-1 capsid in sensing we tested the effect of making HIV-1 by co-expressing a truncated Gag that encodes the first 107 amino acids of capsid fused with luciferase or GFP, alongside wild type Gag-pol. We found that unlike wild type HIV-1, viral particles produced with a mixture of wild type and truncated Gag fused to luciferase or GFP induced a potent IFN response in THP-1 cells and macrophages. Innate immune activation by Gag-fusion HIV-1 was dependent on reverse transcription and DNA sensor cGAS, suggesting activation of an IFN response by viral DNA. Further investigation revealed incorporation of the Gag-luciferase/GFP fusion proteins into viral particles that correlated with subtle defects in wild type Gag cleavage and a diminished capacity to saturate restriction factor TRIM5α, likely due to aberrant particle formation. We propose that expression of the Gag fusion protein disturbs the correct cleavage and maturation of wild type Gag, yielding viral particles that are unable to effectively shield viral DNA from detection by innate sensors including cGAS.
CONCLUSIONS
CONCLUSIONS
These data highlight the crucial role of capsid in innate evasion and support growing literature that disruption of Gag cleavage and capsid formation induces a viral DNA- and cGAS-dependent innate immune response. Together these data demonstrate a protective role for capsid and suggest that antiviral activity of capsid-targeting antivirals may benefit from enhanced innate and adaptive immunity in vivo.
Identifiants
pubmed: 38778414
doi: 10.1186/s12977-024-00643-0
pii: 10.1186/s12977-024-00643-0
doi:
Substances chimiques
cGAS protein, human
EC 2.7.7.-
gag Gene Products, Human Immunodeficiency Virus
0
Nucleotidyltransferases
EC 2.7.7.-
Antiviral Restriction Factors
0
Tripartite Motif Proteins
0
TRIM5 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Carrier Proteins
0
DNA, Viral
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
10Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T006501/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108183
Pays : United Kingdom
Organisme : European Research Council
ID : FP7/2007-2013
Pays : International
Informations de copyright
© 2024. The Author(s).
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