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Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals
BACKGROUND: Inosine triphosphatase (ITPase) is encoded by the polymorphic gene ITPA and maintains low intracellular levels of the inosine nucleotides ITP and dITP. The most frequently reported polymorphisms are ITPA c.94C>A (rs 1127354) and ITPA c. 124+21 A>C (rs7270101). Some nucleoside-analo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260219/ https://www.ncbi.nlm.nih.gov/pubmed/22272297 http://dx.doi.org/10.1371/journal.pone.0030175 |
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author | Bierau, Jörgen Bakker, Jaap A. Schippers, Jolanda A. Grashorn, Janine A. C. Lindhout, Martijn Lowe, Selwyn H. Paulussen, Aimée D. C. Verbon, Annelies |
author_facet | Bierau, Jörgen Bakker, Jaap A. Schippers, Jolanda A. Grashorn, Janine A. C. Lindhout, Martijn Lowe, Selwyn H. Paulussen, Aimée D. C. Verbon, Annelies |
author_sort | Bierau, Jörgen |
collection | PubMed |
description | BACKGROUND: Inosine triphosphatase (ITPase) is encoded by the polymorphic gene ITPA and maintains low intracellular levels of the inosine nucleotides ITP and dITP. The most frequently reported polymorphisms are ITPA c.94C>A (rs 1127354) and ITPA c. 124+21 A>C (rs7270101). Some nucleoside-analogues used in the treatment of HIV-seropositive (HIV+) patients are potential substrates for ITPase. Therefore, the frequency of ITPA SNPs and ITPase activity were studied in a population of HIV+-patients. METHODS: The study population consisted of 222 patients, predominantly Caucasian males, >95% using HAART. Erythrocyte ITPase activity was determined by measuring the formation of IMP from ITP. ITPA genotype was determined by sequencing genomic DNA. Distribution of ITPase activity, genotype-phenotype correlation and allele frequencies were compared to 198 control subjects. The effect of nucleoside analogues on ITPase activity was studied using lymphoblastic T-cell cultures and human recombinant ITPase. Enzyme kinetic experiments were performed on erythrocyte ITPase from HIV+ patients and controls. RESULTS: No difference was observed in the allele frequencies between the HIV+-cohort (± HAART) and the control population. HIV+ carriers of the wild type and ITPA c.94C>A had significantly lower ITPase activities than control subjects with the same genotype (p<0.005). This was not observed in ITPA c. 124+21 A>C carriers. Nucleoside analogues did not affect ITPase activity in cell culture and human recombinant ITPase. Conclusion: ITPA population genetics were identical in HIV+ and control populations. However, the majority of HIV+-patients had decreased erythrocyte ITPase activity compared to controls, probably due to decreased amounts of ITPase protein. It seems unlikely that ITPase activity is decreased due to nucleoside analogues (HAART). Long-term effects of HIV-infection altering ITPase protein expression or stability may explain the phenomenon observed. |
format | Online Article Text |
id | pubmed-3260219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32602192012-01-23 Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals Bierau, Jörgen Bakker, Jaap A. Schippers, Jolanda A. Grashorn, Janine A. C. Lindhout, Martijn Lowe, Selwyn H. Paulussen, Aimée D. C. Verbon, Annelies PLoS One Research Article BACKGROUND: Inosine triphosphatase (ITPase) is encoded by the polymorphic gene ITPA and maintains low intracellular levels of the inosine nucleotides ITP and dITP. The most frequently reported polymorphisms are ITPA c.94C>A (rs 1127354) and ITPA c. 124+21 A>C (rs7270101). Some nucleoside-analogues used in the treatment of HIV-seropositive (HIV+) patients are potential substrates for ITPase. Therefore, the frequency of ITPA SNPs and ITPase activity were studied in a population of HIV+-patients. METHODS: The study population consisted of 222 patients, predominantly Caucasian males, >95% using HAART. Erythrocyte ITPase activity was determined by measuring the formation of IMP from ITP. ITPA genotype was determined by sequencing genomic DNA. Distribution of ITPase activity, genotype-phenotype correlation and allele frequencies were compared to 198 control subjects. The effect of nucleoside analogues on ITPase activity was studied using lymphoblastic T-cell cultures and human recombinant ITPase. Enzyme kinetic experiments were performed on erythrocyte ITPase from HIV+ patients and controls. RESULTS: No difference was observed in the allele frequencies between the HIV+-cohort (± HAART) and the control population. HIV+ carriers of the wild type and ITPA c.94C>A had significantly lower ITPase activities than control subjects with the same genotype (p<0.005). This was not observed in ITPA c. 124+21 A>C carriers. Nucleoside analogues did not affect ITPase activity in cell culture and human recombinant ITPase. Conclusion: ITPA population genetics were identical in HIV+ and control populations. However, the majority of HIV+-patients had decreased erythrocyte ITPase activity compared to controls, probably due to decreased amounts of ITPase protein. It seems unlikely that ITPase activity is decreased due to nucleoside analogues (HAART). Long-term effects of HIV-infection altering ITPase protein expression or stability may explain the phenomenon observed. Public Library of Science 2012-01-17 /pmc/articles/PMC3260219/ /pubmed/22272297 http://dx.doi.org/10.1371/journal.pone.0030175 Text en Bierau et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Bierau, Jörgen Bakker, Jaap A. Schippers, Jolanda A. Grashorn, Janine A. C. Lindhout, Martijn Lowe, Selwyn H. Paulussen, Aimée D. C. Verbon, Annelies Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals |
title | Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals |
title_full | Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals |
title_fullStr | Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals |
title_full_unstemmed | Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals |
title_short | Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals |
title_sort | erythrocyte inosine triphosphatase activity is decreased in hiv-seropositive individuals |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260219/ https://www.ncbi.nlm.nih.gov/pubmed/22272297 http://dx.doi.org/10.1371/journal.pone.0030175 |
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