title: In vivo functions of CPSF6 for HIV-1 as revealed by HIV-1 capsid evolution in HLA-B27-positive subjects.
abstract: The host protein CPSF6 possesses a domain that can interact with the HIV-1 capsid (CA) protein. CPSF6 has been implicated in regulating HIV-1 nuclear entry. However, its functional significance for HIV-1 replication has yet to be firmly established. Here we provide evidence for two divergent functions of CPSF6 for HIV-1 replication in vivo. We demonstrate that endogenous CPSF6 exerts an inhibitory effect on naturally occurring HIV-1 variants in individuals carrying the HLA-B27 allele. Conversely, we find a strong selective pressure in these individuals to preserve CPSF6 binding, while escaping from the restrictive activity by CPSF6. This active maintenance of CPSF6 binding during HIV-1 CA evolution in vivo contrasts with the in vitro viral evolution, which can reduce CPSF6 binding to evade from CPSF6-mediated restriction. Thus, these observations argue for a beneficial role of CPSF6 for HIV-1 in vivo. CPSF6-mediated restriction renders HIV-1 less dependent or independent from TNPO3, RanBP2 and Nup153, host factors implicated in HIV-1 nuclear entry. However, viral evolution that maintains CPSF6 binding in HLA-B27+ subjects invariably restores the ability to utilize these host factors, which may be the major selective pressure for CPSF6 binding in vivo. Our study uncovers two opposing CA-dependent functions of CPSF6 in HIV-1 replication in vivo; however, the benefit for binding CPSF6 appears to outweigh the cost, providing support for a vital function of CPSF6 during HIV-1 replication in vivo.
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, United States of America.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Henning
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, United States of America.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Dubose
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Mallori J
authors.initials: MJ
authors.lastname: Burse
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, United States of America.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamashita
mesh_terms: D002213:Capsid / Q000276:immunology*; D019143:Evolution, Molecular; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000502:physiology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D057131:Immune Evasion / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D015796:HLA-B27 Antigen; C450562:cleavage factor Im, human; D039221:mRNA Cleavage and Polyadenylation Factors