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A Novel Phenotype Links HIV-1 Capsid Stability to cGAS-Mediated DNA Sensing.

Authors :
Siddiqui MA
Saito A
Halambage UD
Ferhadian D
Fischer DK
Francis AC
Melikyan GB
Ambrose Z
Aiken C
Yamashita M
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.)

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