Generic Portal

TY - JOUR

T1 - Genetic variation in Trex1 affects HIV-1 disease progression

AU - Booiman, Thijs

AU - Setiawan, Laurentia C.

AU - Kootstra, Neeltje A.

PY - 2014

Y1 - 2014

N2 - 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. 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. 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. 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

AB - 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. 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. 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. 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

U2 - 10.1097/QAD.0000000000000436

DO - 10.1097/QAD.0000000000000436

M3 - Article

C2 - 25162766

VL - 28

SP - 2517

EP - 2521

JO - AIDS (London, England)

JF - AIDS (London, England)

SN - 0269-9370

IS - 17

ER -