Independent proviral and antiviral host factors recognize the same capsid protein in divergent human herpesviruses

Journal article

Intrinsic cellular factors that inhibit herpesvirus infection remain incompletely defined. Here, we identify TRIM5α as a restriction factor for herpes simplex virus type 1 (HSV-1). TRIM5α-mediated restriction requires its ubiquitin ligase activity, PRY-SPRY domain, and the ability to oligomerize. Mechanistically, we show that TRIM5α directly engages capsid protein VP19C and promotes the stability of the VP19C-VP23 complex and its nuclear accumulation. VP19C also activates NF-κB synergistically with TRIM5α and independently. HSV-1 counteracts this host defense by triggering proteasome-dependent TRIM5α degradation. In addition, we show that Cyclophilin A (CypA), which is incorporated into HSV-1 virions, also binds to VP19C, but enhances infection. As with HIV-1 and orthopoxviruses, the proviral activity of CypA is disrupted by cyclosporin A (CsA), but unlike the situation with these other viruses, the proviral activity of CypA is independent of TRIM5α. Notably, CsA and its non-immunosuppressive derivatives also exhibit anti-HSV-1 activity in neuronal cell lines, suggesting a potential therapy for HSV-1 encephalitis. TRIM5α and CypA also interact with orthologs of VP19C in other alpha, beta and gamma human herpesviruses. These findings reveal two distinct host pathways acting on the herpesvirus capsid and provide a foundation for comparing how TRIM5α and CypA modulate infection of unrelated virus families, offering new directions to identify shared principles of host recognition and viral evasion.

Authors: Zhao, Y; Probert, S; Birkel, J; Liu, X; Shi, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PLoS Pathogens
• Volume: 22
• Issue: 7
• Pages: e1014376-e1014376
• Publication date: 2026-07-08
• Acceptance date: 2026-06-12
• DOI: 10.1371/journal.ppat.1014376
• EISSN: 1553-7374
• ISSN: 1553-7366
• Language: English
• Keywords: Host (biology); Herpes simplex virus; Ubiquitin ligase; Host factor; Cyclophilin A; Capsid; Cypa; Viral replication; Virus