Interplay between HIV entry and transportin-SR2 dependency.

Wannes Thys, Stéphanie De Houwer, Jonas Demeulemeester, Oliver Taltynov, Renée Vancraenenbroeck, Melanie Gérard, Jan De Rijck, Rik Gijsbers, Frauke Christ, Zeger Debyser

Laboratory of Molecular Virology and Gene Therapy, Katholieke Universiteit Leuven, Kapucijnenvoer 33, VCTB+5, B-3000 Leuven, Flanders, Belgium.

Retrovirology 2011

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Transportin-SR2 (TRN-SR2, TNPO3, transportin 3) was previously identified as an interaction partner of human immunodeficiency virus type 1 (HIV-1) integrase and functions as a nuclear import factor of HIV-1. A possible role of capsid in transportin-SR2-mediated nuclear import was recently suggested by the findings that a chimeric HIV virus, carrying the murine leukemia virus (MLV) capsid and matrix proteins, displayed a transportin-SR2 independent phenotype, and that the HIV-1 N74D capsid mutant proved insensitive to transportin-SR2 knockdown. Our present analysis of viral specificity reveals that TRN-SR2 is not used to the same extent by all lentiviruses. The DNA flap does not determine the TRN-SR2 requirement of HIV-1. We corroborate the TRN-SR2 independent phenotype of the chimeric HIV virus carrying the MLV capsid and matrix proteins. We reanalyzed the HIV-1 N74D capsid mutant in cells transiently or stably depleted of transportin-SR2 and confirm that the N74D capsid mutant is independent of TRN-SR2 when pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G). Remarkably, although somewhat less dependent on TRN-SR2 than wild type virus, the N74D capsid mutant carrying the wild type HIV-1 envelope required TRN-SR2 for efficient replication. By pseudotyping with envelopes that mediate pH-independent viral uptake including HIV-1, measles virus and amphotropic MLV envelopes, we demonstrate that HIV-1 N74D capsid mutant viruses retain partial dependency on TRN-SR2. However, this dependency on TRN-SR2 is lost when the HIV N74D capsid mutant is pseudotyped with envelopes mediating pH-dependent endocytosis, such as the VSV-G and Ebola virus envelopes. Here we discover a link between the viral entry of HIV and its interaction with TRN-SR2. Our data confirm the importance of TRN-SR2 in HIV-1 replication and argue for careful interpretation of experiments performed with VSV-G pseudotyped viruses in studies on early steps of HIV replication including the role of capsid therein.

Citation

Wannes Thys, Stéphanie De Houwer, Jonas Demeulemeester, Oliver Taltynov, Renée Vancraenenbroeck, Melanie Gérard, Jan De Rijck, Rik Gijsbers, Frauke Christ, Zeger Debyser. Interplay between HIV entry and transportin-SR2 dependency. Retrovirology. 2011;8:7