Date Published: January 9, 2014
Publisher: Public Library of Science
Author(s): Matthew S. Henning, Brittany N. Dubose, Mallori J. Burse, Christopher Aiken, Masahiro Yamashita, Hans-Georg Krausslich.
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.
An essential part of the HIV-1 lifecycle is the transfer of its genetic material from the cytoplasm into the nucleus for subsequent integration into the host genome. In actively proliferating cells, breakdown of the nuclear membrane during mitosis ensures viral access to the host chromosomes. However, HIV-1 and other lentiviruses share the ability to efficiently infect non-dividing cells –. This necessitates a mechanism of hijacking the cellular transport machinery in order for HIV-1 to cross the intact nuclear envelope through nuclear pores , . Understanding the mechanism of HIV-1 nuclear entry is crucial , , as this is the property that enables HIV-1 to infect such critical target cell types in vivo as resting or partially activated CD4+ T cells ,  as well as tissue macrophages .
Here we provide evidence for two divergent functions of CPSF6. We demonstrate that endogenous CPSF6 exerts a direct inhibitory effect on naturally occurring HIV-1 variants in individuals with HLA-B27. However, we find a strong selective pressure in these individuals to preserve CPSF6 binding while escaping from the restrictive activity by CPSF6, arguing for a beneficial role of CPSF6 for in vivo HIV-1 replication.