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Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of IFN-α.

Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of IFN-α.
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Akiyama H, Ramirez NP, Gibson G, Kline C, Watkins S, Ambrose Z, Gummuluru S,


Akiyama H, Ramirez NP, Gibson G, Kline C, Watkins S, Ambrose Z, Gummuluru S, (click to view)

Akiyama H, Ramirez NP, Gibson G, Kline C, Watkins S, Ambrose Z, Gummuluru S,

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Journal of virology 2017 08 09() pii 10.1128/JVI.00972-17

Abstract

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.

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