한빛사 논문
Kyusik Kima, Ann Dauphina, Sevnur Komurlub, Sean M. McCauleya, Leonid Yurkovetskiya, Claudia Carbonea, William E. Diehla, Caterina Strambio-De-Castilliaa, Edward M. Campbellb,c & Jeremy Lubana,d,*
aProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
bDepartment of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
cInfectious Disease and Immunology Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
dDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA
*Correspondence to Jeremy Luban.
Abstract
The HIV-1 capsid (CA) protein lattice encases viral genomic RNA and regulates steps essential to target-cell invasion 1. Cyclophilin A (CypA) has interacted with the CA of lentiviruses related to HIV-1 for millions of years 2,3,4,5,6,7. Disruption of the CA−CypA interaction decreases HIV-1 infectivity in human cells 8,9,10,11,12 but stimulates infectivity in non-human primate cells 13,14,15. Genetic and biochemical data suggest that CypA protects HIV-1 from a CA-specific restriction factor in human cells 16,17,18,19,20. Discovery of the CA-specific restriction factor tripartite-containing motif 5α (TRIM5α) 21 and multiple, independently derived, TRIM5−CypA fusion genes 4,5,15,22,23,24,25,26 pointed to human TRIM5α being the CypA-sensitive restriction factor. However, HIV-1 restriction by human TRIM5α in tumour cell lines is minimal 21 and inhibition of such activity by CypA has not been detected 27. Here, by exploiting reverse genetic tools optimized for primary human blood cells, we demonstrate that disruption of the CA−CypA interaction renders HIV-1 susceptible to potent restriction by human TRIM5α, with the block occurring before reverse transcription. Endogenous TRIM5α associated with virion cores as they entered the cytoplasm, but only when the CA−CypA interaction was disrupted. These experiments resolve the long-standing mystery of the role of CypA in HIV-1 replication by demonstrating that this ubiquitous cellular protein shields HIV-1 from previously inapparent restriction by human TRIM5α.
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