Inosine Triphosphate Pyrophosphohydrolase Expression: Decreased in leukocytes of HIV-infected patients using combination antiretroviral therapy

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. Design: 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.

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