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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 E1
  • Iwatani, Yasumasa2, 3
  • Shioda, Tatsuo1
  • 1 Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. , (Japan)
  • 2 Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan. , (Japan)
  • 3 Division of Basic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. , (Japan)
Type
Published Article
Journal
AIDS Research and Human Retroviruses
Publisher
Mary Ann Liebert
Publication Date
Jun 01, 2020
Volume
36
Issue
6
Pages
513–521
Identifiers
DOI: 10.1089/AID.2019.0250
PMID: 31941344
Source
Medline
Keywords
Language
English
License
Unknown

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.

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