In Vivo Functions of CPSF6 for HIV-1 as Revealed by HIV-1 Capsid Evolution in HLA-B27-Positive Subjects

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. © 2014 henning et al.