title: Inhibition of microtubules and dynein rescues human immunodeficiency virus type 1 from owl monkey TRIMCyp-mediated restriction in a cellular context-specific fashion.
abstract: IFN-induced restriction factors can significantly affect the replicative capacity of retroviruses in mammals. TRIM5α (tripartite motif protein 5, isoform α) is a restriction factor that acts at early stages of the virus life cycle by intercepting and destabilizing incoming retroviral cores. Sensitivity to TRIM5α maps to the N-terminal domain of the retroviral capsid proteins. In several New World and Old World monkey species, independent events of retrotransposon-mediated insertion of the cyclophilin A (CypA)-coding sequence in the trim5 gene have given rise to TRIMCyp (also called TRIM5-CypA), a hybrid protein that is active against some lentiviruses in a species-specific fashion. In particular, TRIMCyp from the owl monkey (omkTRIMCyp) very efficiently inhibits human immunodeficiency virus type 1 (HIV-1). Previously, we showed that disrupting the integrity of microtubules (MTs) and of cytoplasmic dynein complexes partially rescued replication of retroviruses, including HIV-1, from restriction mediated by TRIM5α. Here, we showed that efficient restriction of HIV-1 by omkTRIMCyp was similarly dependent on the MT network and on dynein complexes, but in a context-dependent fashion. When omkTRIMCyp was expressed in human HeLa cells, restriction was partially counteracted by pharmacological agents targeting MTs or by small interfering RNA-mediated inhibition of dynein. The same drugs (nocodazole and paclitaxel) also rescued HIV-1 from restriction in cat CRFK cells, although to a lesser extent. Strikingly, neither nocodazole, paclitaxel nor depletion of the dynein heavy chain had a significant effect on the restriction of HIV-1 in an owl monkey cell line. These results suggested the existence of cell-specific functional interactions between MTs/dynein and TRIMCyp.
authors.affiliation: Laboratory of Retrovirology, Department of Medical Biology and BioMed Research Group, Université du Québec à Trois-Rivières, 3351 Boulevard des Forges, Trois-Rivières, Quebec G9A 5H7, Canada.
authors.forename: Paulina
authors.initials: P
authors.lastname: Pawlica
authors.affiliation: Laboratory of Retrovirology, Department of Medical Biology and BioMed Research Group, Université du Québec à Trois-Rivières, 3351 Boulevard des Forges, Trois-Rivières, Quebec G9A 5H7, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dufour
authors.affiliation: Laboratory of Retrovirology, Department of Medical Biology and BioMed Research Group, Université du Québec à Trois-Rivières, 3351 Boulevard des Forges, Trois-Rivières, Quebec G9A 5H7, Canada.
authors.forename: Lionel
authors.initials: L
authors.lastname: Berthoux
mesh_terms: D000818:Animals; D016645:Aotidae; D002352:Carrier Proteins / Q000494:pharmacology*; D002415:Cats; D002460:Cell Line; D045744:Cell Line, Tumor; D021984:Cyclophilin A / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000821:virology; D004398:Dyneins / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D011993:Recombinant Fusion Proteins; D004398:Dyneins; D021984:Cyclophilin A