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Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection

Author

Listed:
  • Guochao Wei

    (University of Colorado School of Medicine)

  • Naseer Iqbal

    (University of Colorado School of Medicine)

  • Valentine V. Courouble

    (The Scripps Research Institute)

  • Ashwanth C. Francis

    (Florida State University
    Emory University)

  • Parmit K. Singh

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Arpa Hudait

    (The University of Chicago)

  • Arun S. Annamalai

    (University of Colorado School of Medicine)

  • Stephanie Bester

    (University of Colorado School of Medicine)

  • Szu-Wei Huang

    (University of Colorado School of Medicine
    National Cancer Institute)

  • Nikoloz Shkriabai

    (University of Colorado School of Medicine)

  • Lorenzo Briganti

    (University of Colorado School of Medicine)

  • Reed Haney

    (University of Colorado School of Medicine)

  • Vineet N. KewalRamani

    (National Cancer Institute)

  • Gregory A. Voth

    (The University of Chicago)

  • Alan N. Engelman

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Gregory B. Melikyan

    (Emory University)

  • Patrick R. Griffin

    (The Scripps Research Institute)

  • Francisco Asturias

    (University of Colorado School of Medicine)

  • Mamuka Kvaratskhelia

    (University of Colorado School of Medicine)

Abstract

Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage with biologically relevant mature HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices. Structural studies revealed that multivalent CPSF6 assembly is mediated by LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. In infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results establish previously undescribed mechanisms of virus-host interactions and antiviral action.

Suggested Citation

  • Guochao Wei & Naseer Iqbal & Valentine V. Courouble & Ashwanth C. Francis & Parmit K. Singh & Arpa Hudait & Arun S. Annamalai & Stephanie Bester & Szu-Wei Huang & Nikoloz Shkriabai & Lorenzo Briganti , 2022. "Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33662-6
    DOI: 10.1038/s41467-022-33662-6
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    References listed on IDEAS

    as
    1. Gongpu Zhao & Juan R. Perilla & Ernest L. Yufenyuy & Xin Meng & Bo Chen & Jiying Ning & Jinwoo Ahn & Angela M. Gronenborn & Klaus Schulten & Christopher Aiken & Peijun Zhang, 2013. "Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics," Nature, Nature, vol. 497(7451), pages 643-646, May.
    2. Ashwanth C. Francis & Mariana Marin & Parmit K. Singh & Vasudevan Achuthan & Mathew J. Prellberg & Kristina Palermino-Rowland & Shuiyun Lan & Philip R. Tedbury & Stefan G. Sarafianos & Alan N. Engelma, 2020. "HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    3. John O. Link & Martin S. Rhee & Winston C. Tse & Jim Zheng & John R. Somoza & William Rowe & Rebecca Begley & Anna Chiu & Andrew Mulato & Derek Hansen & Eric Singer & Luong K. Tsai & Rujuta A. Bam & C, 2020. "Clinical targeting of HIV capsid protein with a long-acting small molecule," Nature, Nature, vol. 584(7822), pages 614-618, August.
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    Cited by:

    1. Guangai Xue & Hyun Jae Yu & Cindy Buffone & Szu-Wei Huang & KyeongEun Lee & Shih Lin Goh & Anna T. Gres & Mehmet Hakan Guney & Stefan G. Sarafianos & Jeremy Luban & Felipe Diaz-Griffero & Vineet N. Ke, 2023. "The HIV-1 capsid core is an opportunistic nuclear import receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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