A hallmark of human immunodeficiency virus type 1 (HIV-1) infection 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 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 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 and CD4 T cells in and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon 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 , was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27 and CD169, suggesting productive infection of CD169 myeloid cells While cell-free HIV-1 infection of IFN-α-treated CD4 T cells was robustly decreased, initiation of infection in via coculture with CD169 IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in and in to attenuate a type I IFN-induced antiviral state. HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN). Although type I IFN induces an antiviral state in many cell types , HIV-1 can replicate via mechanisms that have remained unclear. In this study, we tested 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 a subsequent increase in CD169-dependent virus entry. Furthermore, extensive colocalization of viral Gag and CD169 was observed in lymph nodes of infected pigtailed macaques, suggesting productive infection of CD169 cells Treatment of dendritic cell (DC)-T cell cocultures with IFN-α upregulated CD169 expression on DCs and rescued HIV-1 infection of CD4 T cells in , suggesting that HIV-1 exploits CD169 to attenuate type I IFN-induced restrictions.