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

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, Reed Haney, Vineet N. KewalRamani, Gregory A. Voth, Alan N. Engelman, Gregory B. Melikyan, Patrick R. Griffin, Francisco Asturias and Mamuka Kvaratskhelia ()
Additional contact information
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
Parmit K. Singh: Dana-Farber Cancer Institute
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
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33662-6

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