ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression.
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.


CONCLUSIONS
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.
Ballana
Ester
E
Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Senserrich
Jordi
J
Pauls
Eduardo
E
Faner
Rosa
R
Mercader
Josep Maria
JM
Uyttebroeck
Frédéric
F
Palou
Eduard
E
Mena
Maria Pau
MP
Grau
Eulalia
E
Clotet
Bonaventura
B
Ruiz
Lidia
L
Telenti
Amalio
A
Ciuffi
Angela
A
Esté
José A
JA
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015967:Gene Expression Regulation, Viral; D056726:Genetic Association Studies; D005816:Genetic Complementation Test; D015658:HIV Infections / Q000235:genetics* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D015810:Linkage Disequilibrium; D008221:Lymphoid Tissue / Q000821:virology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics*
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C406241:POLR1H protein, human; D034741:RNA, Small Interfering; C444639:RNF39 protein, human