TY - JOUR T1 - Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA JF - bioRxiv DO - 10.1101/838011 SP - 838011 AU - Rebecca P. Sumner AU - Lauren Harrison AU - Emma Touizer AU - Thomas P. Peacock AU - Matthew Spencer AU - Lorena Zuliani-Alvarez AU - Greg J. Towers Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/11/838011.abstract N2 - 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 is not a strong inducer of IFN we have hypothesised that its capsid 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 and primary human macrophages that was dependent on viral DNA and cGAS. 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. ER -