title: Erythrocyte inosine triphosphatase activity is decreased in HIV-seropositive individuals.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands. jorgen.bierau@mumc.nl
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Bakker
authors.forename: Jolanda A
authors.initials: JA
authors.lastname: Schippers
authors.forename: Janine A C
authors.initials: JA
authors.lastname: Grashorn
authors.forename: Martijn
authors.initials: M
authors.lastname: Lindhout
authors.forename: Selwyn H
authors.initials: SH
authors.lastname: Lowe
authors.forename: Aimée D C
authors.initials: AD
authors.lastname: Paulussen
authors.forename: Annelies
authors.initials: A
authors.lastname: Verbon
mesh_terms: D000483:Alleles; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006679:HIV Seropositivity / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000737:chemistry / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D000097630:Inosine Triphosphatase
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase