Akiyama Hisashi, Ramirez Nora-Guadalupe Pina, Gibson Gregory, Kline Christopher, Watkins Simon, Ambrose Zandrea, Gummuluru Suryaram
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
Center for Biologic Imaging and Department of Cell Biology and Molecular Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Virol. 2017 Oct 13;91(21). doi: 10.1128/JVI.00972-17. Print 2017 Nov 1.
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.
1型人类免疫缺陷病毒（HIV-1）感染的一个标志是慢性免疫激活并伴有I型干扰素（IFN）产生。尽管I型干扰素在许多细胞类型中诱导抗病毒状态，但HIV-1能够通过尚不清楚的机制进行复制。我们最近鉴定出一种I型干扰素诱导蛋白CD169，它是树突状细胞（DC）上的HIV-1附着因子，能够介导CD4 T细胞的有效感染。由于巨噬细胞上的CD169表达也由I型干扰素诱导，我们推测I型干扰素诱导的CD169可能促进髓系细胞和CD4 T细胞中的HIV-1有效感染，从而抵消I型干扰素的抗病毒作用。支持这一假设的是，在IFN-α处理的THP-1单核细胞样细胞中，HIV-1或鼠白血病病毒Env（MLV-Env）假型化的HIV-1颗粒感染增强，这种增强主要依赖于病毒进入步骤中CD169介导的增强，这一现象在IFN-α处理的原代单核细胞衍生巨噬细胞（MDM）的HIV-1感染中也有体现。此外，与未感染的猕猴相比，感染携带HIV-1逆转录酶的猿猴免疫缺陷病毒（SIV）（RT-SHIV）的猪尾猕猴淋巴结中，I型干扰素诱导的免疫激活标志物CD169的表达增强，有趣的是，p27和CD169有广泛的共定位，表明CD169髓系细胞发生了有效感染。虽然IFN-α处理的CD4 T细胞的无细胞HIV-1感染显著降低，但通过与CD169 IFN-α处理的DC共培养启动感染可恢复感染，这表明HIV-1利用CD169在和中减弱I型干扰素诱导的抗病毒状态。人类的HIV-1感染会导致以包括I型干扰素（IFN）在内的促炎细胞因子水平升高为特征的免疫激活。尽管I型干扰素在许多细胞类型中诱导抗病毒状态，但HIV-1能够通过尚不清楚的机制进行复制。在本研究中，我们测试了CD169（一种I型干扰素诱导的HIV-1附着因子）抵消I型干扰素抗病毒作用的假设。通过上调CD169以及随后增加依赖CD169的病毒进入，在IFN-α处理的髓系细胞中挽救了HIV-1感染。此外，在感染的猪尾猕猴淋巴结中观察到病毒Gag和CD169广泛共定位，表明CD169细胞发生了有效感染。用IFN-α处理树突状细胞（DC）-T细胞共培养物会上调DC上的CD169表达，并挽救CD4 T细胞的HIV-1感染，这表明HIV-1利用CD169减弱I型干扰素诱导的限制。
