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Here, we identify TRIM5\u03b1 as a restriction factor for herpes simplex virus type 1 (HSV-1). TRIM5\u03b1-mediated restriction requires its ubiquitin ligase activity, PRY\u2013SPRY domain, and the ability to oligomerize. Mechanistically, we show that TRIM5\u03b1 directly engages capsid protein VP19C and promotes the stability of the VP19C\u2013VP23 complex and its nuclear accumulation. VP19C also activates NF-\u03baB synergistically with TRIM5\u03b1 and independently. HSV-1 counteracts this host defense by triggering proteasome-dependent TRIM5\u03b1 degradation. In addition, we show that\u00a0Cyclophilin\u00a0A (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 TRIM5\u03b1. 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. TRIM5\u03b1 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 TRIM5\u03b1 and CypA modulate infection of unrelated virus families, offering new directions to identify shared principles of host recognition and viral evasion.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014376","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:29:01Z","timestamp":1783531741000},"page":"e1014376","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Independent proviral and antiviral host factors recognize the same capsid protein in divergent human herpesviruses"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4348-0588","authenticated-orcid":true,"given":"Yiqi","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Probert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Birkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia Shulan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangyan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4701-5560","authenticated-orcid":true,"given":"Yongxu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3730-9955","authenticated-orcid":true,"given":"Geoffrey L.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"ppat.1014376.ref001","article-title":"The cycle of human herpes simplex virus infection: virus transport and immune control","author":"AL Cunningham","year":"2006","journal-title":"J Infect 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