Background: A hallmark of HIV-1 infection in vivo is chronic immune activation concomitant with type I interferon (IFN-I) production. Although IFN-Is induce an antiviral state in many cell types, HIV-1 can replicate even in the presence of IFN-Is in vivo. We have recently identified the IFN-I-inducible protein CD169 as an HIV-1 receptor on myeloid dendritic cells that can mediate robust infection of CD4+ T cells in trans. Since CD169 expression is also induced by IFN-Is on macrophages, we hypothesized that CD169 induced by IFN-I could facilitate productive HIV-1 infection in macrophages in cis and thus offset antiviral effects of IFN-Is.
Methods: To investigate the effect of IFN-Is on HIV-1 replication in myeloid cells, a monocyte cell line, THP-1 or primary monocyte-derived macrophages (MDMs) were treated with IFNα for 48 hours and infected with HIVΔenv-luc reporter virus pseudotyped with HIV-1 Lai (HIV/Lai) or VSV-G (HIV/G) glycoproteins, or replication competent HIV-luc. HIV-1 fusion was measured by the conventional Vpr-BlaM assay. To investigate if CD169+ myeloid cells are productively infected in vivo, lymph nodes (LNs) from pigtailed macaques chronically infected with RT-SHIVmne027 were stained for p27gag and CD169.
Results: As reported previously, HIV/G infection was severely attenuated in IFN-treated-THP-1. Surprisingly, however, replication of HIV/Lai was enhanced in IFN-treated-THP-1 than in untreated THP-1. We found that HIV/Lai fusion was greatly enhanced in IFN-treated-THP-1, while that of HIV/G was severely attenuated. This enhanced fusion and infection depended on CD169 since pretreatment with αCD169 blocking antibody abrogated the enhancement of virus fusion and replication in IFN-treated-THP-1. IFNα treatment of MDMs also up-regulated CD169 and HIV-1 fusion in treated MDMs was enhanced (2-fold) in a CD169-dependent manner. Interestingly, CD169 enhanced virus replication in MDMs even in the presence of IFNα (>2-fold higher compared to MDMs pretreated with αCD169 blocking antibody). Finally, LNs from SHIV-infected macaques showing signatures of immune activation contained more CD169+ cells than those of uninfected animals and, intriguingly, a large proportion of p27gag+ cells were also CD169+.
Conclusions: These studies suggest that HIV-1 has exploited CD169 to attenuate IFN-I-induced antiviral state in myeloid cells.