Affordable Access

Access to the full text

The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1

Authors
  • Saito, Akatsuki1
  • Sultana, Tahmina1
  • Ode, Hirotaka2
  • Nohata, Kyotaro1
  • Samune, Yoshihiro1
  • Nakayama, Emi E.1
  • Iwatani, Yasumasa2, 3
  • Shioda, Tatsuo1
  • 1 Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • 2 Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
  • 3 Division of Basic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Type
Published Article
Journal
AIDS Research and Human Retroviruses
Publisher
Mary Ann Liebert
Publication Date
May 28, 2020
Volume
36
Issue
6
Pages
513–521
Identifiers
DOI: 10.1089/aid.2019.0250
PMID: 31941344
PMCID: PMC7262650
Source
PubMed Central
Keywords
License
Green

Abstract

Binding of HIV-1 capsid (CA) to cleavage and polyadenylation specificity factor 6 (CPSF6) is hypothesized to provide a significant fitness advantage to in vivo viral replication, explaining why CA-CPSF6 interactions are strictly conserved in primate lentiviruses. We recently identified a Q4R mutation in CA after propagation of an interferon (IFN)-β-hypersensitive CA mutant, RGDA/Q112D (H87R, A88G, P90D, P93A and Q112D) virus, in IFN-β-treated cells. The Q4R substitution conferred significant IFN-β resistance to the RGDA/Q112D virus by affecting several properties of the virus, including the sensitivity to myxovirus resistance protein B (MxB), the kinetics of reverse transcription, and the initiation of uncoating. Notably, the Q4R substitution restored the CPSF6 interaction of the RGDA/Q112D virus. To better understand how the Q4R substitution modulated the CA-CPSF6 interaction, we generated a series of CA mutants harboring substitutions at the 4th and 112th residues. In contrast to the effect in the RGDA/Q112D background, the Q4R substitution diminished CA-CPSF6 interaction in an otherwise wild-type virus. Our genetic and structural analyses revealed that while either the Q4R or Q112D substitution impaired CA-CPSF6 interaction, the combination of these substitutions restored this interaction. These results suggest that the 4th and 112th residues in HIV-1 CA cooperatively modulate CA-CPSF6 interactions, further highlighting the tremendous levels of plasticity in primate lentivirus CA, which is one of the barriers to antiretroviral therapy in HIV-1-infected individuals.

Report this publication

Statistics

Seen <100 times