Interactions with Commensal and Pathogenic Bacteria Induce HIV-1 Latency in Macrophages through Altered Transcription Factor Recruitment to the Long Terminal Repeat

Macrophages are infected by human immunodeficiency virus type 1 (HIV-1) in vivo and contribute to both viral spread and pathogenesis. Recent human and animal studies suggest that HIV-1-infected macrophages serve as a reservoir that contributes to HIV-1 persistence during antiretroviral therapy. The ability of macrophages to serve as persistent viral reservoirs is likely influenced by the local tissue microenvironment, including interactions with pathogenic and commensal microbes. Here, we show that the sexually transmitted pathogen Neisseria gonorrhoeae (gonococcus [GC]) and the gut-associated microbe Escherichia coli, which encode ligands for both Toll-like receptor 2 (TLR2) and TLR4, repressed HIV-1 replication in macrophages and thereby induced a state reminiscent of viral latency. This repression was mediated by signaling through TLR4 and the adaptor protein Toll/interleukin 1 (IL-1) receptor domain-containing adapter-inducing beta interferon (IFN) (TRIF) and was associated with increased production of type I interferons. Inhibiting TLR4 signaling, blocking type 1 interferon, or knocking down TRIF reversed lipopolysaccharide (LPS)- and gonococcus-mediated repression of HIV-1. Finally, the repression of HIV-1 in macrophages was associated with the recruitment of interferon regulatory factor 8 (IRF8) to the interferon-stimulated response element (ISRE) downstream of the HIV-1 5′ long terminal repeat (LTR). Our data indicate that IRF8 is responsible for repression of HIV-1 replication in macrophages in response to TRIF-dependent signaling during N. gonorrhoeae and E. coli coinfection. These findings highlight the potential role of macrophages as HIV-1 reservoirs, as well as the roles of the tissue microenvironment and coinfections as modulators of HIV-1 persistence. IMPORTANCE The major barrier toward the eradication of HIV-1 infection is the presence of a small reservoir of latently infected cells, which include CD4(+) T cells and macrophages that escape immune-mediated clearance and the effects of antiretroviral therapy. There remain crucial gaps in our understanding of the molecular mechanisms that lead to transcriptionally silent or latent HIV-1 infection of macrophages. The significance of our research is in identifying microenvironmental factors, such as commensal and pathogenic microbes, that can contribute to the establishment and maintenance of latent HIV-1 infection in macrophages. It is hoped that identifying key processes contributing to HIV-1 persistence in macrophages may ultimately lead to novel therapeutics to eliminate latent HIV-1 reservoirs in vivo.