GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants

• Published in: Science advances Vol. 9; no. 28; p. eadg2955
• Main Authors: Aoki, Manabu, Aoki-Ogata, Hiromi, Bulut, Haydar, Hayashi, Hironori, Takamune, Nobutoki, Kishimoto, Naoki, Tanaka, Hiroki, Higashi-Kuwata, Nobuyo, Hattori, Shin-Ichiro, Das, Debananda, Venkateswara Rao, Kalapala, Iwama, Kazuya, Davis, David A, Hasegawa, Kazuya, Murayama, Kazutaka, Yarchoan, Robert, Ghosh, Arun K, Pau, Alice K, Machida, Shinichi, Misumi, Shogo, Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 14.07.2023
• Subjects: Antiviral Agents; Biomedicine and Life Sciences; HIV Integrase - genetics; HIV-1 - genetics; Humans; Nuclear Localization Signals - genetics; SciAdv r-articles; Virology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adg2955

Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV ) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC of 130 femtomolar. When cells were exposed to HIV IN-containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS's putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142-bound HIV 's PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant-harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.