Keratin-72 restricts HIV-1 infection in resting CD4⁺ T cells by sequestering capsids in intermediate filaments

The accessory protein Vpx from the red-capped mangabey or mandrill SIV (SIV_rcm/mnd-2) lineage has been reported to increase HIV-1 infection in resting CD4⁺ T cells without affecting SAMHD1, a known target of Vpx in HIV-1 infection. This indicates that Vpx, in addition to SAMHD1, circumvents other restriction factors for lentiviruses. To identify potential restriction factors, this study examined cellular proteins interacting with Vpx_rcm and found that keratin-72 (KRT72), an intermediate filament (IF) protein expressed in resting CD4⁺ T cells, is a host antiviral factor targeted by Vpx. Vpx_rcm/mnd-2 lineages could strongly promote KRT72 degradation, resulting in increased HIV-1 infection in resting CD4⁺ T cells. We discovered that KRT72 restricts HIV-1 replication by sequestering incoming HIV-1 capsids in cytoplasmic IFs. With KRT72, the capsid cores of HIV-1 become attached to IFs, and their trafficking toward the nucleus is inhibited. In contrast, without KRT72, HIV-1 capsids are transported to the nucleus, leading to high levels of integrated HIV-1 DNA. Thus, KRT72 is a Vpx-counteracted antiviral factor that binds the incoming capsids to cytoplasmic IFs, restricting HIV-1 infection in resting CD4⁺ T cells.