Abstract
BackgroundAs 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.MethodsSamples 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.Results325 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.ConclusionsLEDGF/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.
Highlights
As Lens epithelium-derived growth factor (LEDGF/p75) is an important co-factor involved in human immunodeficiency virus (HIV)-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs)
We focused on the association of genetic variation in the full coding region+39UTR of the LEDGF/p75 gene and HIV-1 disease progression and on the link of genetic variants with LEDGF/p75 and HRP2 mRNA expression levels
Classification of patients according to disease progression was based on broadly applied clinical definitions [39,40,41,42,43]: LTNP elite controllers (LTNP-EC) are long-term non-progressors (10 year follow-up, CD4 .500cells/mL) maintaining an undetectable viral load without antiretroviral therapy (n = 48), LTNP viremic controllers (LTNP-VC) are long-term non-progressors harboring less than 2000 HIV RNA copies/ml without therapy in 75% of the measurements (n = 63), viremic non-controllers (LTNP-NC) are long-term non-progressors with a viral load between 2000 and 10,000 copies/ml (n = 66)
Summary
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). 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. Acquired Immunodeficiency Syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is one of the major infectious diseases with 34 million people affected world-wide [1]. Short- and long-term side-effects often challenge life-long antiviral treatment, prompting the need for new therapeutic strategies. This search has mainly been focussed on targeting viral enzymes as reverse transcriptase, protease and more recently integrase [3]. Further unravelling the host – virus interaction leads to better understanding of viral dynamics and disease progression, and paves the way to validate new targets in the treatment of HIV-1 [5]. An increasing number of co-factors is being studied in the course of new strategies against HIV-1 infection [6]
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