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

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. Host proteins CPSF6, NUP153, and SEC24C are vital for HIV-1 infection. They bind to the viral capsid protein and contribute to shuttling of virions through the cytoplasm (SEC24C), import into the nucleus (NUP153 and CPSF6) and subsequent trafficking to preferred integration sites (CPSF6). Here, Wei et al. combine structural, biochemical and virological assays to emphasize the importance of prion-like low complexity domains surrounding short phenylalanine-glycine regions in binding and increasing the avidity when interacting with viral capsid.