Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression

PLoS One. 2012;7(11):e50204. doi: 10.1371/journal.pone.0050204. Epub 2012 Nov 30.

Abstract

Background: As Lens epithelium-derived growth factor (LEDGF/p75) is an important co-factor involved in HIV-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs). Few data are available on the genetic variability of LEDGF/p75 and the influence on HIV disease in vivo. This study evaluated the relation between LEDGF/p75 genetic variation, mRNA expression and HIV-1 disease progression in order to guide future clinical use of LEDGINs.

Methods: Samples were derived from a therapy-naïve cohort at Ghent University Hospital and a Spanish long-term-non-progressor cohort. High-resolution melting curve analysis and Sanger sequencing were used to identify all single nucleotide polymorphisms (SNPs) in the coding region, flanking intronic regions and full 3'UTR of LEDGF/p75. In addition, two intronic tagSNPs were screened based on previous indication of influencing HIV disease. LEDGF/p75 mRNA was quantified in patient peripheral blood mononuclear cells (PBMC) using RT-qPCR.

Results: 325 samples were investigated from patients of Caucasian (n = 291) and African (n = 34) origin, including Elite (n = 49) and Viremic controllers (n = 62). 21 SNPs were identified, comprising five in the coding region and 16 in the non-coding regions and 3'UTR. The variants in the coding region were infrequent and had no major impact on protein structure according to SIFT and PolyPhen score. One intronic SNP (rs2737828) was significantly under-represented in Caucasian patients (P<0.0001) compared to healthy controls (HapMap). Two SNPs showed a non-significant trend towards association with slower disease progression but not with LEDGF/p75 expression. The observed variation in LEDGF/p75 expression was not correlated with disease progression.

Conclusions: LEDGF/p75 is a highly conserved protein. Two non-coding polymorphisms were identified indicating a correlation with disease outcome, but further research is needed to clarify phenotypic impact. The conserved coding region and the observed variation in LEDGF/p75 expression are important characteristics for clinical use of LEDGINs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Amino Acid Sequence
  • Conserved Sequence
  • Disease Progression*
  • Exons
  • Female
  • HIV Infections / diagnosis
  • HIV Infections / genetics*
  • HIV Infections / pathology*
  • HIV Infections / virology
  • HIV-1*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Introns
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Open Reading Frames
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • RNA, Messenger / genetics
  • Sequence Analysis, DNA

Substances

  • 3' Untranslated Regions
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • lens epithelium-derived growth factor

Grants and funding

This work was partly supported by the Flemish Agency for Innovation by Science and Technology (CellCoVir - IWT file nr 60813). Linos Vandekerckhove is supported by the National Fund for Scientific Research – Belgium as Principal Investigator. The Spanish RIS cohort and HIV BioBank are integrated in the Spanish AIDS Research Network supported by Instituto de Salud Carlos III (Grant RD06/0006/0035) and Fundación para la Investigación y Prevención del SIDA en España (FIPSE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.