title: Inosine Triphosphate Pyrophosphohydrolase Expression: Decreased in Leukocytes of HIV-Infected Patients Using Combination Antiretroviral Therapy.
abstract: OBJECTIVE
  In HIV-infected patients, the enzyme Inosine triphosphate pyrophosphohydrolase (ITPase), involved in purine nucleotide homeostasis, was found to be decreased in erythrocytes. Since purine analogues are pivotal in the HIV treatment, a better understanding of ITPase expression in CD4 lymphocytes may lead to better understanding of nucleotide metabolism and (adverse) effects.
  
  
  METHODS
  Cross-sectional, cohort, observational study.
  
  
  METHODS
  HIV-infected and control patients above 18 years were included. All DNA samples were genotyped for the 2 functional ITPA SNPs; c.94C>A (rs1127354) and g.IVS+21A>C (rs7270101). ITPase expression was determined by flow cytometry in all leukocyte subsets.
  
  
  RESULTS
  Fifty-nine HIV-infected patients and 50 controls were included. Leukocyte subtype distribution showed no difference in monocytes and granulocytes, but lymphocytes were higher in HIV-infected patients (P < 0.001). ITPase expression was highest in activated monocytes and lowest in lymphocytes. In HIV-infected patients, the percentage of ITPase positive cells was less in all leukocyte and lymphocyte subsets compared with controls (P < 0.01). In HIV-infected patients, 97.4% of CD4 lymphocytes were ITPase positive versus 99.9% in controls (P = 0.002) and 85.9% versus 99.6% of CD8 lymphocytes (P < 0.0001), respectively. Stratification according to genotype revealed no significant differences in ITPase expression in leukocytes in HIV-infected and control patients.
  
  
  CONCLUSIONS
  HIV-infection seems to be interfering with the nucleotide metabolism in leukocytes, including CD4 lymphocytes, by decreasing ITPase expression, independently of ITPA genotype. Given that active metabolites of purine-analogue reverse transcriptase inhibitors are potential substrates for ITPase, these results warrant further research towards effectiveness and adverse events of purine analogues and ITPase activity.
authors: *Department of Internal Medicine, Division of Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands;†Department of Clinical Chemistry and Hematology, Zuyderland Medical Center, Heerlen, the Netherlands;‡Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, the Netherlands;Departments of §Medical Microbiology;‖Internal Medicine, Division of Infectious Diseases, Research School CAPHRI, Maastricht University Medical Center, Maastricht, the Netherlands;¶Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands; and#Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, the Netherlands.
authors: N Chantal
authors: NC
authors: Peltenburg
authors: Mathie P G
authors: MP
authors: Leers
authors: Jaap A
authors: JA
authors: Bakker
authors: Selwyn H
authors: SH
authors: Lowe
authors: Wim H M
authors: WH
authors: Vroemen
authors: Aimée D C
authors: AD
authors: Paulussen
authors: Bianca J C
authors: BJ
authors: van den Bosch
authors: Jörgen
authors: J
authors: Bierau
authors: Annelies
authors: A
authors: Verbon
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D004359:Drug Therapy, Combination; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D000097630:Inosine Triphosphatase
chemical_list: D019380:Anti-HIV Agents; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase