Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA.

Detection of viral DNA by cyclic GMP-AMP synthase (cGAS) is a first line of defence leading to the production of type I interferon (IFN). As HIV-1 replication is not a strong inducer of IFN, we hypothesised that an intact capsid physically cloaks viral DNA from cGAS. To test this, we generated defective viral particles by treatment with HIV-1 protease inhibitors or by genetic manipulation of gag. These viruses had defective Gag cleavage, reduced infectivity and diminished capacity to saturate TRIM5α. Importantly, unlike wild-type HIV-1, infection with cleavage defective HIV-1 triggered an IFN response in THP-1 cells that was dependent on viral DNA and cGAS. An IFN response was also observed in primary human macrophages infected with cleavage defective viruses. Infection in the presence of the capsid destabilising small molecule PF-74 also induced a cGAS-dependent IFN response. These data demonstrate a protective role for capsid and suggest that antiviral activity of capsid- and protease-targeting antivirals may benefit from enhanced innate and adaptive immunity in vivo. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Citation

Rebecca P Sumner, Lauren Harrison, Emma Touizer, Thomas P Peacock, Matthew Spencer, Lorena Zuliani-Alvarez, Greg J Towers. Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA. The EMBO journal. 2020 Oct 15;39(20):e103958

Mesh Tags

Substances

PMID: 32852081

search → result