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 - Funding Information:
We thank the NIH AIDS repository for reagents. A.S. P.H. and F.D.-G. are supported by an NIH AI087390 grant to F.D.-G. Anti-Nopp140 antibodies were a kind gift from Dr. T. Meier. GS-CA1 was a donation of Stephen Yant (Gilead Sciences). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. A.S. P.H. S.M. L.M.S. H.J.Y. designed, performed and analyzed experiments. J.F.H. KE.L. V.N.KR. designed the experiments. F.D.-G. designed experiments and wrote the paper. The authors declare no competing interests.
Funding Information:
We thank the NIH AIDS repository for reagents. A.S., P.H., and F.D.-G. are supported by an NIH AI087390 grant to F.D.-G. Anti-Nopp140 antibodies were a kind gift from Dr. T. Meier. GS-CA1 was a donation of Stephen Yant (Gilead Sciences). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
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
AN - SCOPUS:85121851483
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 1
M1 - 103593
ER -
