Abstract
BackgroundDendritic cells (DCs) are among the first cells to encounter HIV-1 and play important roles in viral transmission and pathogenesis. Immature DCs allow productive HIV-1 replication and long-term viral dissemination. The pro-inflammatory factor lipopolysaccharide (LPS) induces DC maturation and enhances the efficiency of DC-mediated HIV-1 transmission. Type I interferon (IFN) partially inhibits HIV-1 replication and cell-cell transmission in CD4+ T cells and macrophages. Tetherin is a type I IFN-inducible restriction factor that blocks HIV-1 release and modulates CD4+ T cell-mediated cell-to-cell transmission of HIV-1. However, the role of type I IFN and tetherin in HIV-1 infection of DCs and DC-mediated viral transmission remains unknown.ResultsWe demonstrated that IFN-alpha (IFNα)-induced mature DCs restricted HIV-1 replication and trans-infection of CD4+ T cells. Tetherin expression in monocyte-derived immature DCs was undetectable or very low. High levels of tetherin were transiently expressed in LPS- and IFNα-induced mature DCs, while HIV-1 localized into distinct patches in these DCs. Knockdown of induced tetherin in LPS- or IFNα-matured DCs modestly enhanced HIV-1 transmission to CD4+ T cells, but had no significant effect on wild-type HIV-1 replication in mature DCs. Intriguingly, we found that HIV-1 replication in immature DCs induced significant tetherin expression in a Nef-dependent manner.ConclusionsThe restriction of HIV-1 replication and transmission in IFNα-induced mature DCs indicates a potent anti-HIV-1 response; however, high levels of tetherin induced in mature DCs cannot significantly restrict wild-type HIV-1 release and DC-mediated HIV-1 transmission. Nef-dependent tetherin induction in HIV-1-infected immature DCs suggests an innate immune response of DCs to HIV-1 infection.
Highlights
Dendritic cells (DCs) are among the first cells to encounter HIV-1 and play important roles in viral transmission and pathogenesis
The restriction of HIV-1 replication and transmission in IFNa-induced mature DCs indicates a potent anti-HIV-1 response; high levels of tetherin induced in mature DCs cannot significantly restrict wild-type HIV-1 release and DC-mediated HIV-1 transmission
This study suggested that type I IFN produced by plasmacytoid DCs (pDC) during viral infection may stimulate neighboring cells to express tetherin, which interacts with immunoglobulin-like transcript 7 (ILT7) on pDCs to down-modulate IFN and cytokine responses
Summary
Dendritic cells (DCs) are among the first cells to encounter HIV-1 and play important roles in viral transmission and pathogenesis. The role of type I IFN and tetherin in HIV-1 infection of DCs and DC-mediated viral transmission remains unknown. DCs play an important role in innate immune recognition and activation during HIV infection [1,2]. Immature DCs allow productive HIV-1 replication and long-term viral dissemination [6,7,8]. DC-mediated dissemination of HIV-1 occurs through the dissociable processes of trans- and cis-infection, depending on whether productive viral infection is initiated in DCs [6]. Productive HIV-1 infection of DCs can induce DC maturation and trigger antiviral innate immunity through type I IFN responses [14]
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