TY - JOUR
T1 - GS-CA1 and lenacapavir stabilize the HIV-1 core and modulate the core interaction with cellular factors
AU - Selyutina, Anastasia
AU - Hu, Pan
AU - Miller, Sorin
AU - Simons, Lacy M.
AU - Yu, Hyun Jae
AU - Hultquist, Judd F.
AU - Lee, Kyeong Eun
AU - KewalRamani, Vineet N.
AU - Diaz-Griffero, Felipe
N1 - Publisher Copyright:
© 2021
PY - 2022/1/21
Y1 - 2022/1/21
N2 - 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.
AB - 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.
KW - Biological sciences
KW - Immunology
KW - Virology
UR - http://www.scopus.com/inward/record.url?scp=85121851483&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121851483&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103593
DO - 10.1016/j.isci.2021.103593
M3 - Article
C2 - 35005542
AN - SCOPUS:85121851483
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 1
M1 - 103593
ER -