title: Naturally occurring capsid substitutions render HIV-1 cyclophilin A independent in human cells and TRIM-cyclophilin-resistant in Owl monkey cells.
abstract: In this study, we asked if a naturally occurring HIV-1 variant exists that circumvents CypA dependence in human cells. To address this issue, we sought viruses for CypA independence using Debio-025, a cyclosporine A (CsA) analog that disrupts CypA-capsid interaction. Surprisingly, viral variants from the Main group replicate even in the presence of the drug. Sequencing analyses revealed that these viruses encode capsid substitutions within the CypA-binding site (V86P/H87Q/I91V/M96I). When we introduced these substitutions into viruses that normally rely on CypA for replication, these mutants no longer depended on CypA, suggesting that naturally occurring capsid substitutions obviate the need for CypA. This is the first demonstration that isolates from the Main group naturally develop CypA-independent strategies to replicate in human cells. Surprisingly, we found that these capsid substitutions render HIV-1 capable of infecting Owl monkey (OMK) cells that highly restrict HIV-1. OMK cell resistance to HIV-1 is mediated via TRIM-Cyp, which arose from a retrotransposition of CypA into the TRIM5 alpha gene. Interestingly, saturation experiments suggest that the Pro86/Gln87/Val91/Ile96 capsid core is "invisible" to TRIM-Cyp. This study demonstrates that specific capsid substitutions can release HIV-1 from both CypA dependence in human cells and TRIM-Cyp restriction in monkey cells.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Chatterji
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bobardt
authors.forename: Robyn
authors.initials: R
authors.lastname: Stanfield
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Luke A
authors.initials: LA
authors.lastname: Pallansch
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Ward
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Jones
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
authors.forename: Pietro
authors.initials: P
authors.lastname: Scalfaro
authors.forename: Jean-Maurice
authors.initials: JM
authors.lastname: Dumont
authors.forename: Kamel
authors.initials: K
authors.lastname: Besseghir
authors.forename: Brigitte
authors.initials: B
authors.lastname: Rosenwirth
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Gallay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016645:Aotidae; D001665:Binding Sites; D015153:Blotting, Western; D002213:Capsid / Q000737:chemistry*; D036022:Capsid Proteins / Q000737:chemistry*; D002460:Cell Line; D021984:Cyclophilin A / Q000737:chemistry*; D021983:Cyclophilins / Q000737:chemistry; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D018626:Retroelements; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036022:Capsid Proteins; D008565:Membrane Proteins; D018626:Retroelements; C114030:TRAT1 protein, human; D021984:Cyclophilin A; D021983:Cyclophilins