Journal of virology 2017 08 09() pii 10.1128/JVI.00972-17
A hallmark of HIV-1 infection in vivo is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicate in vivo via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein CD169 as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4(+) T cells in trans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in cis and CD4(+) T cells in trans and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or MLV-Env pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, an observation phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation in vivo, was enhanced in lymph nodes from RT-SHIV-infected pigtailed macaques, compared to uninfected macaques, and interestingly, there was extensive co-localization of p27(gag) and CD169, suggesting productive infection of CD169(+) myeloid cells in vivo. While cell-free HIV-1 infection of IFN-α-treated CD4(+) T cells was robustly decreased, initiation of infection in trans via co-culture with CD169(+) IFN-α-treated DCs restored infection suggesting that HIV-1 exploits CD169 in cis and in trans to attenuate a type I IFN-induced antiviral state.Structured AbstractHIV-1 infection in human causes immune activation characterized by elevated levels of pro-inflammatory cytokines including type I interferons (IFN). Although type I IFN induces an antiviral state in many cell types in vitro, HIV-1 can replicate in vivo via mechanisms that have remained unclear. In this report, we test the hypothesis that CD169, a type I IFN-inducible HIV-1 attachment factor, offsets antiviral effects of type I IFN. Infection of HIV-1 was rescued in IFN-α-treated myeloid cells via upregulation of CD169 and subsequent increase in CD169-dependent virus entry. Furthermore, extensive co-localization of viral Gag and CD169 was observed in lymph nodes of infected pigtailed macaques, suggesting productive infection of CD169(+) cells in vivo. Treatment of dendritic cell (DC) – T cell co-cultures with IFN-α, upregulated CD169 expression on DCs and rescued HIV-1 infection of CD4(+) T cells in trans suggesting that HIV-1 exploits CD169 to attenuate type I IFN-induced restrictions.