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Clin Microbiol Infect. 2019 May 31. pii: S1198-743X(19)30274-5. doi: 10.1016/j.cmi.2019.05.015. [Epub ahead of print]

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

Author information

1
AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain; Hospital Clínic- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: fdiezf@isciii.es.
2
AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
3
Molecular Virology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
4
Unidad de Bioinformática y Bioestadística, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
5
HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain.
6
Servicio de Medicina Interna-Infecciosas, Hospital Universitario "Son Espases", Palma de Mallorca, Spain.
7
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France.
8
Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, Sevilla, Spain; Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocío, Sevilla, Spain; INB-ELIXIR-es, FPS, Hospital Virgen del Rocío, Sevilla, Spain.
9
Functional Genetics of Infectious Diseases, Pasteur Institute, Paris, France.
10
AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain; Hospital Clínic- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: ppalcami@isciii.es.

Abstract

OBJECTIVES:

The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4+ T-cell counts and partially control viral replication for 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 microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 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 major histocompatibility complex 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 = 2.11 × 10-6). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity 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.

KEYWORDS:

CAV1; Caveolae; Exome; HIV-1; Lipid rafts; Long-term non-progressor; Single nucleotide polymorphism; UBXN6; VCP

PMID:
31158522
DOI:
10.1016/j.cmi.2019.05.015

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