Sec24C is an HIV-1 host dependency factor crucial for virus replication

Early events of the human immunodeficiency virus 1 (HIV-1) lifecycle, such as post-entry virus trafficking, uncoating and nuclear import, are poorly characterized because of limited understanding of virus-host interactions. Here, we used mass spectrometry-based proteomics to delineate cellular binding partners of curved HIV-1 capsid lattices and identified Sec24C as an HIV-1 host dependency factor. Gene deletion and complementation in Jurkat cells revealed that Sec24C facilitates infection and markedly enhances HIV-1 spreading infection. Downregulation of Sec24C in HeLa cells substantially reduced HIV-1 core stability and adversely affected reverse transcription, nuclear import and infectivity. Live-cell microscopy showed that Sec24C co-trafficked with HIV-1 cores in the cytoplasm during virus ingress. Biochemical assays demonstrated that Sec24C directly and specifically interacted with hexameric capsid lattices. A 2.3-angstrom resolution crystal structure of Sec24C(228-242) in the complex with a capsid hexamer revealed that the Sec24C FG-motif bound to a pocket comprised of two adjoining capsid subunits. Combined with previous data(1-4), our findings indicate that a capsid-binding FG-motif is conserved in unrelated proteins present in the cytoplasm (Sec24C), the nuclear pore (Nup153; refs.(3,4)) and the nucleus (CPSF6; refs.(1,2)). We propose that these virus-host interactions during HIV-1 trafficking across different cellular compartments are crucial for productive infection of target cells.

Automated summary

This study identified Sec24C as a host dependency factor for HIV-1 infection, showing that it facilitates viral trafficking, stability, and infectivity. The interactions between Sec24C and capsid lattices are crucial for productive infection of target cells across different cellular compartments. The study provides insights into the early events of the HIV-1 lifecycle and the role of host factors in virus-host interactions.