Back to Search
Start Over
A Novel Phenotype Links HIV-1 Capsid Stability to cGAS-Mediated DNA Sensing.
- Source :
-
Journal of virology [J Virol] 2019 Jul 30; Vol. 93 (16). Date of Electronic Publication: 2019 Jul 30 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- The HIV-1 capsid executes essential functions that are regulated by capsid stability and host factors. In contrast to increasing knowledge on functional roles of capsid-interacting host proteins during postentry steps, less is known about capsid stability and its impact on intracellular events. Here, using the antiviral compound PF-3450074 (PF74) as a probe for capsid function, we uncovered a novel phenotype of capsid stability that has a profound effect on innate sensing of viral DNA by the DNA sensor cGAS. A single mutation, R143A, in the capsid protein conferred resistance to high concentrations of PF74, without affecting capsid binding to PF74. A cell-free assay showed that the R143A mutant partially counteracted the capsid-destabilizing activity of PF74, pointing to capsid stabilization as a resistance mechanism for the R143A mutant. In monocytic THP-1 cells, the R143A virus, but not the wild-type virus, suppressed cGAS-dependent innate immune activation. These results suggest that capsid stabilization improves the shielding of viral DNA from innate sensing. We found that a naturally occurring transmitted founder (T/F) variant shares the same properties as the R143A mutant with respect to PF74 resistance and DNA sensing. Imaging assays revealed delayed uncoating kinetics of this T/F variant and the R143A mutant. All these phenotypes of this T/F variant were controlled by a genetic polymorphism located at the trimeric interface between capsid hexamers, thus linking these capsid-dependent properties. Overall, this work functionally connects capsid stability to innate sensing of viral DNA and reveals naturally occurring phenotypic variation in HIV-1 capsid stability. IMPORTANCE The HIV-1 capsid, which is made from individual viral capsid proteins (CA), is a target for a number of antiviral compounds, including the small-molecule inhibitor PF74. In the present study, we utilized PF74 to identify a transmitted/founder (T/F) strain that shows increased capsid stability. Interestingly, PF74-resistant variants prevented cGAS-dependent innate immune activation under a condition where the other T/F strains induced type I interferon. These observations thus reveal a new CA-specific phenotype that couples capsid stability to viral DNA recognition by cytosolic DNA sensors.<br /> (Copyright © 2019 American Society for Microbiology.)
- Subjects :
- Amino Acid Sequence
Anti-HIV Agents pharmacology
Capsid Proteins genetics
Capsid Proteins metabolism
Cell Line, Tumor
Disease Resistance
HIV Infections drug therapy
HIV-1 drug effects
Humans
Indoles pharmacology
Mutation
Phenylalanine analogs & derivatives
Phenylalanine pharmacology
Protein Stability
Capsid metabolism
DNA, Viral
HIV Infections metabolism
HIV Infections virology
HIV-1 physiology
Host-Pathogen Interactions
Nucleotidyltransferases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 93
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 31167922
- Full Text :
- https://doi.org/10.1128/JVI.00706-19