Association of a single nucleotide polymorphism in ubxn6 gene with long term non progression phenotype in hiv-positive individuals

Abstract Objectives The long-term non-progressors (LTNP) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 + T-cell counts and partially control viral replicationfor years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals. Methods DNA microarraysand exome sequencingwere used for genotyping about 240,000 functional polymorphisms throughout more than 20,000 human genes. The allele frequenciesof 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells. Results Several SNPs located within the MHC region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 ( UBXN6 ) surpassed the statistical significance of these markers after Bonferroni correction(q=2.11x10 -6 ). An uncommon allelic frequencyof rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6-knockdown experiments caused an increase of CAV1 expression and its accumulation in the plasma membrane of different cell types. In vitro infection of these cells with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replicationcapacity compared with their corresponding wild type cells expressing UBXN6. Conclusions A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6-knockdown affected CAV1 turnover and HIV-1 replication capacity.