AIDS research and human retroviruses 2017 01 31() doi 10.1089/AID.2016.0273
Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyper-responsiveness to subsequent Toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1-priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 prior to activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by addition of LPS. HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ (r=0.679, P=0.003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced TNF protein expression and release. Increased TNF production was limited to productively infected cells. Specific STAT1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication. .