Innate immune memory promotes neural damage in the ART suppressed HIV infected brain

ABSTRACT The widespread use of antiretroviral therapy (ART) in developed countries has modified HIV infection from a terminal illness to what is now largely a manageable chronic infection. Even when HIV replication is suppressed with ART, people infected with HIV present with a chronic inflammatory state that is thought to contribute to the development of neurologic and psychiatric co-morbid conditions. A growing body of evidence is implicating the innate immune system with sensitization of the brain to neurological damage associated with HIV infection and other neurodegenerative conditions. This non-resolving inflammatory/immune response sensitizes and primes the brain for any subsequent inflammatory event, and is thought to be a form of innate immune memory in which microglia adapt their phenotype depending on the stimulus they are exposed to, and the frequency with which they are exposed to that stimulus. This adaptation is a form of innate immune memory that can be associated with long-lasting molecular reprogramming that can either enhance or suppress the microglial response to subsequent stimuli. The impact of HIV infection, and ART on microglial reprogramming is unknown. Here we have identified the sphingomyelin hydrolase neutral sphingomyelinase2 (nSMase2) generated ceramide as a critical regulator of the innate immune response to ART suppressed HIV infection.