Journal Article

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

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

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 50, issue 7, pages 1022-1032
Published in print April 2010 | ISSN: 1058-4838
Published online April 2010 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/651114
ZNRD1 (Zinc Ribbon Domain-Containing 1) Is a Host Cellular Factor That Influences HIV-1 Replication and Disease Progression

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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.

Journal Article.  5948 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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