2024-03-28T14:18:40Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/69692022-07-28T07:58:31Zcom_20.500.12105_2060com_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_2061
00925njm 22002777a 4500
dc
Messiaen, Peter
author
De Spiegelaere, Ward
author
Alcamí, José
author
Vervisch, Karen
author
Van Acker, Petra
author
Verhasselt, Bruno
author
Meuwissen, Pieter
author
Calonge, Esther
author
Gonzalez-Fernandez, Nuria
author
Gutierrez-Rodero, Felix
author
Rodriguez-Martín, Carmen
author
Sermijn, Erica
author
Poppe, Bruce
author
Vogelaers, Dirk
author
Verhofstede, Chris
author
Vandekerckhove, Linos
author
2012-11-30
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.
PLoS One. 2012;7(11):e50204
1932-6203
http://hdl.handle.net/20.500.12105/6969
23226247
10.1371/journal.pone.0050204
1932-6203
PloS one
Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression