The earliest events following mucosal HIV-1 infection, prior to measurable viremia,
remain poorly understood. Here, by detailed necropsy studies, we show that the virus
can rapidly disseminate following mucosal SIV infection of rhesus monkeys and trigger
components of the inflammasome, both at the site of inoculation and at early sites
of distal virus spread. By 24 hr following inoculation, a proinflammatory signature
that lacked antiviral restriction factors was observed in viral RNA-positive tissues.
The early innate response included expression of NLRX1, which inhibits antiviral responses,
and activation of the TGF-β pathway, which negatively regulates adaptive immune responses.
These data suggest a model in which the virus triggers specific host mechanisms that
suppress the generation of antiviral innate and adaptive immune responses in the first
few days of infection, thus facilitating its own replication. These findings have
important implications for the development of vaccines and other strategies to prevent
infection.