HIV 阳性个体的红细胞肌苷三磷酸酶活性降低。
Erythrocyte inosine triphosphatase activity is decreased in HIV-seropositive individuals.
机构信息
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
出版信息
PLoS One. 2012;7(1):e30175. doi: 10.1371/journal.pone.0030175. Epub 2012 Jan 17.
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.
背景
肌苷三磷酸酶（ITPase）由多态基因 ITPA 编码，可维持肌苷核苷酸 ITP 和 dITP 的细胞内低水平。最常报道的多态性是 ITPA c.94C>A（rs1127354）和 ITPA c.124+21 A>C（rs7270101）。一些用于治疗 HIV 阳性（HIV+）患者的核苷类似物是 ITPase 的潜在底物。因此，研究了 HIV+患者人群中 ITPA SNP 和 ITPase 活性的频率。
方法
研究人群由 222 名患者组成，主要为高加索裔男性，95%以上使用 HAART。通过测量 ITP 形成 IMP 来测定红细胞 ITPase 活性。通过测序基因组 DNA 确定 ITPA 基因型。将 ITPase 活性、基因型-表型相关性和等位基因频率的分布与 198 名对照进行比较。使用淋巴母细胞 T 细胞培养和人重组 ITPase 研究核苷类似物对 ITPase 活性的影响。在 HIV+患者和对照的红细胞 ITPase 上进行酶动力学实验。
结果
HIV+ 队列（±HAART）和对照组之间的等位基因频率没有差异。与具有相同基因型的对照相比，野生型和 ITPA c.94C>A 的 HIV+携带者的 ITPase 活性显着降低（p<0.005）。在 ITPA c.124+21 A>C 携带者中没有观察到这种情况。核苷类似物在细胞培养和人重组 ITPase 中均不影响 ITPase 活性。
结论
HIV+ 和对照组的 ITPA 群体遗传学相同。然而，与对照组相比，大多数 HIV+患者的红细胞 ITPase 活性降低，可能是由于 ITPase 蛋白量减少所致。由于核苷类似物（HAART）导致 ITPase 活性降低的可能性似乎不大。HIV 感染对 ITPase 蛋白表达或稳定性的长期影响可能解释了观察到的现象。
Zotero 插件