GS-CA1 and lenacapavir stabilize the HIV-1 core and modulate the core interaction with cellular factors

Anastasia Selyutina, Pan Hu, Sorin Miller, Lacy M. Simons, Hyun Jae Yu, Judd F. Hultquist, Kyeong Eun Lee, Vineet N. KewalRamani, Felipe Diaz-Griffero

Research output: Contribution to journalArticlepeer-review

Abstract

The HIV-1 capsid is the target for the antiviral drugs GS-CA1 and Lenacapavir (GS-6207). We investigated the mechanism by which GS-CA1 and GS-6207 inhibit HIV-1 infection. HIV-1 inhibition by GS-CA1 did not require CPSF6 in CD4+ T cells. Contrary to PF74 that accelerates uncoating of HIV-1, GS-CA1 and GS-6207 stabilized the core. GS-CA1, unlike PF74, allowed the core to enter the nucleus, which agrees with the fact that GS-CA1 inhibits infection after reverse transcription. Unlike PF74, GS-CA1 did not disaggregate preformed CPSF6 complexes in nuclear speckles, suggesting that PF74 and GS-CA1 have different mechanisms of action. GS-CA1 stabilized the HIV-1 core, possibly by inducing a conformational shift in the core; in agreement, HIV-1 cores bearing N74D regained their ability to bind CPSF6 in the presence of GS-CA1. We showed that GS-CA1 binds to the HIV-1 core, changes its conformation, stabilizes the core, and thereby prevents viral uncoating and infection.

Original languageEnglish (US)
Article number103593
JournaliScience
Volume25
Issue number1
DOIs
StatePublished - Jan 21 2022

Keywords

  • Biological sciences
  • Immunology
  • Virology

ASJC Scopus subject areas

  • General

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