Abstract
Detection of viralDNAby cyclicGMP-AMPsynthase (cGAS) is a first line of defence leading to the production of type I interferon (IFN). AsHIV-1 replication is not a strong inducer ofIFN, we hypothesised that an intact capsid physically cloaks viralDNAfromcGAS. To test this, we generated defective viral particles by treatment withHIV-1 protease inhibitors or by genetic manipulation ofgag. These viruses had defective Gag cleavage, reduced infectivity and diminished capacity to saturateTRIM5 alpha. Importantly, unlike wild-typeHIV-1, infection with cleavage defectiveHIV-1 triggered anIFNresponse inTHP-1 cells that was dependent on viralDNAandcGAS. AnIFNresponse was also observed in primary human macrophages infected with cleavage defective viruses. Infection in the presence of the capsid destabilising small moleculePF-74 also induced acGAS-dependentIFNresponse. 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 immunityin vivo.