Abstract
BackgroundInterferon induced transmembrane proteins 1, 2 and 3 (IFITMs) belong to a family of highly related antiviral factors that have been shown to interfere with a large spectrum of viruses including Filoviruses, Coronaviruses, Influenza virus, Dengue virus and HIV-1. In all these cases, the reported mechanism of antiviral inhibition indicates that the pool of IFITM proteins present in target cells blocks incoming viral particles in endosomal vesicles where they are subsequently degraded.ResultsIn this study, we describe an additional mechanism through which IFITMs block HIV-1. In virus-producing cells, IFITMs coalesce with forming virions and are incorporated into viral particles. Expression of IFITMs during virion assembly leads to the production of virion particles of decreased infectivity that are mostly affected during entry in target cells. This mechanism of inhibition is exerted against different retroviruses and does not seem to be dependent on the type of Envelope present on retroviral particles.ConclusionsThe results described here identify a novel mechanism through which IFITMs affect HIV-1 infectivity during the late phases of the viral life cycle. Put in the context of data obtained by other laboratories, these results indicate that IFITMs can target HIV at two distinct moments of its life cycle, in target cells as well as in virus-producing cells. These results raise the possibility that IFITMs could similarly affect distinct steps of the life cycle of a number of other viruses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-014-0103-y) contains supplementary material, which is available to authorized users.
Highlights
Interferon induced transmembrane proteins 1, 2 and 3 (IFITMs) belong to a family of highly related antiviral factors that have been shown to interfere with a large spectrum of viruses including Filoviruses, Coronaviruses, Influenza virus, Dengue virus and HIV-1
Upon exo-RT normalization, virions were used to challenge HeLaP4 cells and viral infectivity was measured by β-galactosidase assay (MAGI) 24 hours afterwards, taking advantage of the HIV-1-LTR-β-Gal reporter stably integrated in these cells (Figure 1C, right graph)
Given that in addition to the direct decrease in viral particles infectivity that we describe here, IFITMs have been previously described to affect the entry of HIV-1 when expressed in target cells [9] and given that the assay of spreading infection does not allow the distinction between these two effects, viral particles retrieved at the end of the culture were normalized by exo-RT activity and used to challenge HeLaP4 cells to determine their intrinsic infectivity in a single round infection assay (Figure 5D)
Summary
Interferon induced transmembrane proteins 1, 2 and 3 (IFITMs) belong to a family of highly related antiviral factors that have been shown to interfere with a large spectrum of viruses including Filoviruses, Coronaviruses, Influenza virus, Dengue virus and HIV-1. In all these cases, the reported mechanism of antiviral inhibition indicates that the pool of IFITM proteins present in target cells blocks incoming viral particles in endosomal vesicles where they are subsequently degraded. The finding that pH-independent viruses can functionally access the cytosol from endosomal vesicles likely explains the broad antiviral effects of IFITMs against these diverse classes of virus [24]
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