{
  "abstract": "Background: Immune non-response to antiretroviral therapy remains a major challenge in HIV-1 management, yet the underlying molecular mechanisms are incompletely understood.\n\nMethods: In this study, we performed comparative quantitative proteomics on samples from immunonon-responsive (INR) and immune-responsive (IR) individuals, identifying the deubiquitinase YOD1 as one of the most significantly upregulated proteins in INR patients, accompanied by hyperactivation of ubiquitin‑proteasome pathways.\n\nResults: Through immunoprecipitation coupled with mass spectrometry, we found that YOD1 associates with the HIV-1 Nef protein, a key viral factor that subverts host immunity. Mechanistically, YOD1 specifically removes K6‑linked polyubiquitin chains from Nef via its catalytic cysteine residue (C155S), thereby preventing proteasomal degradation and dose‑dependently stabilizing Nef protein levels without affecting its transcription. This regulation was selective for Nef, as YOD1 did not alter other HIV‑1 proteins (gp120, Vif, or Tat). In HIV‑1‑infected THP‑1 macrophages and clinical PBMCs from people living with HIV, YOD1 expression correlated positively with Nef levels and viral load; knockdown or catalytic inactivation of YOD1 markedly increased Nef ubiquitination, reduced p24 antigen secretion, and suppressed virus production. Importantly, screening of nutritional compounds revealed that Vitamin C (VC) promotes YOD1 degradation via the ubiquitin‑proteasome pathway, leading to downregulation of Nef, inhibition of HIV‑1 replication, and restoration of CD4+ T‑cell counts. These antiviral and immune‑restorative effects of VC were completely abrogated upon YOD1 depletion, confirming their dependency on YOD1 targeting.\n\nConclusion: Collectively, our findings establish YOD1 as a critical host factor that sustains HIV‑1 Nef stability and viral infectivity through K6‑linked deubiquitination, and they identify Vitamin C as a clinically accessible agent that degrades YOD1, offering a potential adjuvant strategy to improve immune recovery in non‑responding patients.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital, Suzhou Medical College of Soochow University, The Fifth People’s Hospital of Suzhou",
    "Department of Infectious Diseases, Zhangjiagang Hospital Affiliated to Soochow University",
    "Department of Pharmacy, The Affiliated Infectious Diseases Hospital, Suzhou Medical College of Soochow University, The Fifth People’s Hospital of Suzhou",
    "Department of Urology Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University",
    "Department of Tuberculosis, The Affiliated Infectious Diseases Hospital, Suzhou Medical College of Soochow University, The Fifth People’s Hospital of Suzhou"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jin Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Qian Xu"
    },
    {
      "affs": [
        2
      ],
      "name": "Yu Jiang"
    },
    {
      "affs": [
        3
      ],
      "name": "Zhouzhou Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Guiyan Li"
    },
    {
      "affs": [
        4
      ],
      "name": "Minyan Yao"
    },
    {
      "affs": [
        0
      ],
      "name": "Tiantian Gan"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiming Zheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Yujuan Yan"
    },
    {
      "affs": [
        0
      ],
      "name": "Yueping Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Saihong Gu"
    },
    {
      "affs": [
        0
      ],
      "name": "Ming Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Li Zhu"
    },
    {
      "affs": [
        4
      ],
      "name": "Jianping Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chuanwu Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Feng Qian"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9v5g6qaq3f75b.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1936616",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936616/full",
  "id": "9v5g6qaq3f75b",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936616/full",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC581-607"
    ],
    [
      "openalex",
      "2406|HIV Research and Treatment"
    ]
  ],
  "openalex": "W7223367738",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1936616/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/9v5g6qaq3f75b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1936616",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1936616/full"
    },
    {
      "first_seen": "2026-10-30T13:43:11Z",
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      "url": "https://doi.org/10.3389/fimmu.2026.1936616"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2406|HIV Research and Treatment",
      "subfield": "microbiology"
    }
  ],
  "title": "YOD1 stabilizes HIV-1 Nef via K6-linked deubiquitination to promote viral infectivity and impair immune recovery",
  "title_text": "YOD1 stabilizes HIV-1 Nef via K6-linked deubiquitination to promote viral infectivity and impair immune recovery",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:11Z",
  "url": "https://research.draconitic.com/paper/9v5g6qaq3f75b",
  "venue": "Frontiers in Immunology",
  "versions": []
}