Genetic variation in Trex1 affects HIV-1 disease progression.

Abstract

OBJECTIVE:

Three prime repair exonuclease 1 (TREX1) plays a pivotal role in HIV-1 infection. In-vitro studies have shown that TREX1 degrades excess HIV-1 DNA, thereby shielding HIV-1 from recognition by innate immune receptors and preventing a type 1 interferon response. To determine whether TREX1 plays a role in HIV-1 pathogenesis, we analyzed whether genetic variation in Trex1 is associated with the clinical course of HIV-1 infection.

DESIGN/METHODS:

Two tagging single nucleotide polymorphisms (SNPs) in Trex1 were genotyped in a cohort of 304 HIV-1-infected MSM and a cohort of 66 high-risk seronegative individuals. Kaplan-Meier and Cox regression survival analyses were used to analyze the effect of the SNPs on HIV-1 disease progression. In-vitro HIV-1 infection assays and Trex1 mRNA analysis were performed in peripheral blood mononuclear cells (PBMCs) obtained from donors that were genotyped for the tag SNP in Trex1.

RESULTS:

We observed that the minor allele of SNP rs3135941 in Trex1 is associated with faster HIV-1 disease progression. This association was independent of the CCR5-Δ32 genotype and human leukocyte antigen alleles that were previously found to be predictive of disease progression. In addition, we observed an increased HIV-1 replication in PBMC positive for the minor allele of SNP rs3135941.

CONCLUSION:

Our data emphasize the important role of TREX1 in HIV-1 pathogenesis. The association of SNP rs3135941 with accelerated disease progression that we observed might be explained by the increased HIV-1 replication observed in PBMC positive for the minor allele of the SNP.

• Authors: Thijs Booiman, Laurentia C Setiawan, Neeltje A Kootstra
• Journal: AIDS (London, England) (AIDS) Vol. 28 Issue 17 Pg. 2517-21 (Nov 13 2014) ISSN: 1473-5571 [Electronic] England
• PMID: 25162766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoproteins
• Exodeoxyribonucleases
• three prime repair exonuclease 1

Topics

• Cohort Studies
• Disease Progression
• Exodeoxyribonucleases (genetics)
• Gene Frequency
• Genotype
• HIV Infections (genetics, virology)
• HIV-1 (isolation & purification)
• Host-Pathogen Interactions
• Humans
• Male
• Phosphoproteins (genetics)
• Polymorphism, Single Nucleotide