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

  • Sci Adv. 2023 Jul 14;9(28):eadg2955. doi: 10.1126/sciadv.adg2955.
Manabu Aoki  1  2  3 ,  Hiromi Aoki-Ogata  1  3 ,  Haydar Bulut  1 ,  Hironori Hayashi  4  5 ,  Nobutoki Takamune  6 ,  Naoki Kishimoto  6 ,  Hiroki Tanaka  7 ,  Nobuyo Higashi-Kuwata  3 ,  Shin-Ichiro Hattori  3 ,  Debananda Das  1 ,  Kalapala Venkateswara Rao  8 ,  Kazuya Iwama  4  5 ,  David A Davis  9 ,  Kazuya Hasegawa  10 ,  Kazutaka Murayama  11 ,  Robert Yarchoan  9 ,  Arun K Ghosh  8 ,  Alice K Pau  12 ,  Shinichi Machida  7 ,  Shogo Misumi  6 ,  Hiroaki Mitsuya  1  3  13
Affiliations
  • 1. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2. Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan.
  • 3. Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 4. Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Miyagi, Japan.
  • 5. Department of infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
  • 6. Department of Environmental and Molecular Health Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  • 7. Department of Structural Virology, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 8. Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN, USA.
  • 9. Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 10. Structural Biology Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
  • 11. Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan.
  • 12. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 13. Division of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan.
PMID: 37436982 DOI: 10.1126/sciadv.adg2955
Abstract

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 (HIVKGD) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIVKGD was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC50 of 130 femtomolar. When cells were exposed to HIVKGD 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 HIVKGD'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.

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