Tumor Suppressor Cylindromatosis (CYLD) Controls HIV transcription in an NF-κB-dependent manner

Lara Manganaro, Lars Pache, Tobias Herrmann, John Marlett, Young Hwang, Jeffrey Murry, Lisa Miorin, Adrian T. Ting, Renate König, Adolfo García-Sastre, Frederic D. Bushman, Sumit K. Chanda, John A.T. Young, Ana Fernandez-Sesma, Viviana Simon

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Characterizing the cellular factors that play a role in the HIV replication cycle is fundamental to fully understanding mechanisms of viral replication and pathogenesis. Whole-genome small interfering RNA (siRNA) screens have identified positive and negative regulators of HIV replication, providing starting points for investigating new cellular factors. We report here that silencing of the deubiquitinase cylindromatosis protein (CYLD), increases HIV infection by enhancing HIV long terminal repeat (LTR)-driven transcription via the NF-κB pathway. CYLD is highly expressed in CD4+ T lymphocytes, monocyte-derived macrophages, and dendritic cells. We found that CYLD silencing increases HIV replication in T cell lines. We confirmed the positive role of CYLD silencing in HIV infection in primary human CD4+ T cells, in which CYLD protein was partially processed upon activation. Lastly, Jurkat T cells latently infected with HIV (JLat cells) were more responsive to phorbol 12-myristate 13-acetate (PMA) reactivation in the absence of CYLD, indicating that CYLD activity could play a role in HIV reactivation from latency. In summary, we show that CYLD acts as a potent negative regulator of HIV mRNA expression by specifically inhibiting NF-κB driven transcription. These findings suggest a function for this protein in modulating productive viral replication as well as in viral reactivation.

Original languageEnglish (US)
Pages (from-to)7528-7540
Number of pages13
JournalJournal of virology
Volume88
Issue number13
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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