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bioRxiv · 10.1101/838011

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

Sumner, R. P.·Harrison, L.·Touizer, E.·Peacock, T. P.·Spencer, M.·Zuliani-Alvarez, L.·Towers, G. J.
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Abstract

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 TRIM5. 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.

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Sumner, R. P., Harrison, L., Touizer, E., Peacock, T. P., Spencer, M., Zuliani-Alvarez, L., Towers, G. J.. 2019-11-11. Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA. https://doi.org/10.1101/838011

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