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

(2012) PLOS ONE. 7(11).
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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-naive 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.
Keywords
HUMAN-IMMUNODEFICIENCY-VIRUS, STRESS ONCOPROTEIN LEDGF/P75, GROWTH FACTOR/P75, HUMAN-CELLS, IN-VITRO, INTEGRASE, REPLICATION, INFECTION, PROTEIN, MUTATIONS

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MLA
Messiaen, Peter et al. “Characterization of LEDGF/p75 Genetic Variants and Association with HIV-1 Disease Progression.” PLOS ONE 7.11 (2012): n. pag. Print.
APA
Messiaen, P., De Spiegelaere, W., Alcami, J., Vervisch, K., Van Acker, P., Verhasselt, B., Meuwissen, P., et al. (2012). Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression. PLOS ONE, 7(11).
Chicago author-date
Messiaen, Peter, Ward De Spiegelaere, Jose Alcami, Karen Vervisch, Petra Van Acker, Bruno Verhasselt, Pieter Meuwissen, et al. 2012. “Characterization of LEDGF/p75 Genetic Variants and Association with HIV-1 Disease Progression.” Plos One 7 (11).
Chicago author-date (all authors)
Messiaen, Peter, Ward De Spiegelaere, Jose Alcami, Karen Vervisch, Petra Van Acker, Bruno Verhasselt, Pieter Meuwissen, Esther Calonge, Nuria Gonzalez, Felix Gutierrez-Rodero, Carmen Rodriguez-Martín, ERICA SERMIJN, Bruce Poppe, Dirk Vogelaers, Chris Verhofstede, and Linos Vandekerckhove. 2012. “Characterization of LEDGF/p75 Genetic Variants and Association with HIV-1 Disease Progression.” Plos One 7 (11).
Vancouver
1.
Messiaen P, De Spiegelaere W, Alcami J, Vervisch K, Van Acker P, Verhasselt B, et al. Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression. PLOS ONE. 2012;7(11).
IEEE
[1]
P. Messiaen et al., “Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression,” PLOS ONE, vol. 7, no. 11, 2012.
@article{3128596,
  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-naive 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.},
  articleno    = {e50204},
  author       = {Messiaen, Peter and De Spiegelaere, Ward and Alcami, Jose and Vervisch, Karen and Van Acker, Petra and Verhasselt, Bruno and Meuwissen, Pieter and Calonge, Esther and Gonzalez, Nuria and Gutierrez-Rodero, Felix and Rodriguez-Martín, Carmen and SERMIJN, ERICA and Poppe, Bruce and Vogelaers, Dirk and Verhofstede, Chris and Vandekerckhove, Linos},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keywords     = {HUMAN-IMMUNODEFICIENCY-VIRUS,STRESS ONCOPROTEIN LEDGF/P75,GROWTH FACTOR/P75,HUMAN-CELLS,IN-VITRO,INTEGRASE,REPLICATION,INFECTION,PROTEIN,MUTATIONS},
  language     = {eng},
  number       = {11},
  pages        = {9},
  title        = {Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression},
  url          = {http://dx.doi.org/10.1371/journal.pone.0050204},
  volume       = {7},
  year         = {2012},
}

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