Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
BMC Infect Dis. 2013 May 4;13:203. doi: 10.1186/1471-2334-13-203.
Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined.
Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software.
A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-α and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction.
Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.
在接受抗逆转录病毒疗法（ART）的 HIV 感染者中，代谢异常很常见，但这些疾病的生化细节和潜在机制尚未确定。
使用液相或气相色谱和质谱法对 32 名接受基于蛋白酶抑制剂（PI）的 ART 且最低 CD4 计数（<300 个/μl）较低的 HIV 患者和 20 名健康对照者进行了非靶向代谢组学血浆分析。检查了丙型肝炎（HCV）合并感染的影响，以及改变的脂质代谢物与炎症、微生物易位和肝功能标志物之间的关系。使用 dChip、Metaboanalyst 和 MSEA 软件进行无监督层次聚类、主成分分析（PCA）、偏最小二乘判别分析（PLS-DA）、随机森林、途径映射和代谢物集富集分析（MSEA）。
与基于 PI 的 ART 治疗的晚期疾病 HIV 患者与对照者（无论 HCV 血清状态如何）区分的 35 种代谢产物特征图谱映射到脂质、氨基酸和核苷酸代谢（p<0.05，错误发现率（FDR）<0.1）。许多改变的脂质，包括胆汁酸、硫酸甾体、多不饱和脂肪酸和类二十烷酸，是调节代谢和炎症的核受体的配体。改变的脂质的不同簇与炎症标志物（干扰素-α和白细胞介素-6）、微生物易位（脂多糖（LPS）和 LPS 结合蛋白）和肝功能标志物（胆红素）相关（p<0.05）。脂质改变与非酒精性脂肪性肝病（NALFD）中报道的改变有很大重叠。胆汁酸增加与非侵入性肝纤维化标志物（FIB-4、APRI 和 YKL-40）相关，并与酰基辅酶 A，线粒体功能障碍的标志物相关。
接受基于 PI 的 ART 的 HIV 患者的脂质改变与炎症、微生物易位和肝功能标志物相关，这表明减轻失调的固有免疫激活和肝功能障碍的治疗策略可能有益于预防和治疗 HIV 患者的代谢紊乱。
