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ZNRD1 (Zinc Ribbon Domain-Containing 1) Is a Host Cellular Factor That Influences HIV-1 Replication and Disease Progression

Ballana, Ester ; Senserrich, Jordi ; Pauls, Eduardo ; Faner, Rosa ; Mercader, Josep Maria ; Uyttebroeck, Frédéric ; Palou, Eduard ; Mena, Maria Pau ; Grau, Eulalia ; Clotet, Bonaventura ; Ruiz, Lidia ; Telenti, Amalio ; Ciuffi, Angela ; Esté, José A.

In: Clinical Infectious Diseases, 2010, vol. 50, no. 7, p. 1022-1032

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    Titre
    • ZNRD1 (Zinc Ribbon Domain-Containing 1) Is a Host Cellular Factor That Influences HIV-1 Replication and Disease Progression
    Auteur
    • Ballana, Ester. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Senserrich, Jordi. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Pauls, Eduardo. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Faner, Rosa. Laboratori d'Immunobiologia per a la Recerca i Aplicacions Diagnòstiques, Banc de Sang i Teixits, Badalona
    • Mercader, Josep Maria. Barcelona Supercomputing Center, Barcelona, Spain
    • Uyttebroeck, Frédéric. Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Palou, Eduard. Laboratori d'Immunobiologia per a la Recerca i Aplicacions Diagnòstiques, Banc de Sang i Teixits, Badalona
    • Mena, Maria Pau. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Grau, Eulalia. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Clotet, Bonaventura. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Ruiz, Lidia. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    • Telenti, Amalio. Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Ciuffi, Angela. Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland
    • Esté, José A.. Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Clinical Infectious Diseases, 2010, vol. 50, no. 7, p. 1022-1032. University of Chicago Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:293404
    Summary
    Background Human immunodeficiency virus (HIV) takes advantage of multiple host proteins to support its own replication. The gene ZNRD1 (zinc ribbon domain-containing 1) has been identified as encoding a potential host factor that influenced disease progression in HIV-positive individuals in a genomewide association study and also significantly affected HIV replication in a large-scale in vitro short interfering RNA (siRNA) screen. Genes and polymorphisms identified by large-scale analysis need to be followed up by means of functional assays and resequencing efforts to more precisely map causal genes. Methods Genotyping and ZNRD1 gene resequencing for 208 HIV-positive subjects (119 who experienced long-term nonprogression [LTNP] and 89 who experienced normal disease progression) was done by either TaqMan genotyping assays or direct sequencing. Genetic association analysis was performed with the SNPassoc package and Haploview software. siRNA and short hairpin RNA (shRNA) specifically targeting ZNRD1 were used to transiently or stably down-regulate ZNRD1 expression in both lymphoid and nonlymphoid cells. Cells were infected with X4 and R5 HIV strains, and efficiency of infection was assessed by reporter gene assay or p24 assay. Results Genetic association analysis found a strong statistically significant correlation with the LTNP phenotype (single-nucleotide polymorphism rs1048412; P = .0004), independently of HLA-A10 influence. siRNA-based functional analysis showed that ZNRD1 down-regulation by siRNA or shRNA impaired HIV-1 replication at the transcription level in both lymphoid and nonlymphoid cells. Conclusion Genetic association analysis unequivocally identified ZNRD1 as an independent marker of LTNP to AIDS. Moreover, in vitro experiments pointed to viral transcription as the inhibited step. Thus, our data strongly suggest that ZNRD1 is a host cellular factor that influences HIV-1 replication and disease progression in HIV-positive individuals