HIV感染由于其致病性和神经致病性特征而损害外周和中枢免疫系统。驱动HIV-1发病机制和神经发病机制涉及一系列事件,包括代谢失调.此外,HIV亚型特异性变异,特别是关键病毒蛋白的氨基酸序列的改变,已知会影响HIV感染者临床结局的严重程度。然而,特定病毒蛋白中氨基酸序列变异的影响,如病毒蛋白R(Vpr),对HIV感染者中色氨酸(Trp)-犬尿氨酸(Kyn)途径内的代谢物仍不清楚。我们的研究旨在探索Vpr氨基酸序列的变异(特别是在22、41、45和55位,因为这些先前与神经认知功能有关)与外周Trp-Kyn代谢物之间的关系。此外,我们试图通过检查Trp-Kyn代谢与外周炎症之间的联系来阐明Vpr序列变异的系统生物学,作为一种神经致病机制。在这项初步研究中,我们分析了32例(n=32)南非cART初治HIV感染者的独特队列.我们采用Sanger测序来确定血液来源的Vpr氨基酸序列变异,并采用靶向LC-MS/MS代谢组学平台来评估Trp-Kyn代谢产物。比如Trp,Kyn,犬尿氨酸(KA),和喹啉酸(QUIN)。粒子增强比浊法和酶联免疫吸附试验用于测量免疫标志物,hsCRP,IL-6suPAR,NGAL和sCD163。在应用Bonferroni校正(p=0.05/3)并调整协变量(年龄和性别)后,与VprS41和T55组相比,只有VprG41和A55组的QUIN水平接近显著性,分别(所有p=0.023)。多元回归结果显示,41位的Vpr氨基酸变异(adjR2=0.049,β=0.505;p=0.023),55(adjR2=0.126,β=0.444;p=0.023)在调整年龄和性别后显示与QUIN的显着关联。最后,发现在VprG41组中观察到的较高QUIN水平与suPAR相关(r=.588,p=.005)。这些结果共同强调了特定Vpr氨基酸取代在影响QUIN和炎症(特别是suPAR水平)方面的重要性。可能有助于我们理解它们在HIV-1发病机制和神经发病机制中的作用。
HIV infection compromises both the peripheral and central immune systems due to its pathogenic and neuropathogenic features. The mechanisms driving HIV-1 pathogenesis and
neuropathogenesis involve a series of events, including metabolic dysregulation. Furthermore, HIV-subtype-specific variations, particularly alterations in the amino acid sequences of key viral proteins, are known to influence the severity of clinical outcomes in people living with HIV. However, the impact of amino acid sequence variations in specific viral proteins, such as Viral protein R (Vpr), on metabolites within the Tryptophan (Trp)-kynurenine (Kyn) pathway in people living with HIV remains unclear. Our research aimed to explore the relationship between variations in the Vpr amino acid sequence (specifically at positions 22, 41, 45, and 55, as these have been previously linked to neurocognitive function) and peripheral Trp-Kyn metabolites. Additionally, we sought to clarify the systems biology of Vpr sequence variation by examining the link between Trp-Kyn metabolism and peripheral inflammation, as a neuropathogenic mechanism. In this preliminary study, we analyzed a unique cohort of thirty-two (n = 32) South African cART naïve people living with HIV. We employed Sanger sequencing to ascertain blood-derived Vpr amino acid sequence variations and a targeted LC-MS/MS metabolomics platform to assess Trp-Kyn metabolites, such as Trp, Kyn, kynurenic acid (KA), and quinolinic acid (QUIN). Particle-enhanced turbidimetric assay and Enzyme-linked immunosorbent assays were used to measure immune markers, hsCRP, IL-6, suPAR, NGAL and sCD163. After applying Bonferroni corrections (p =.05/3) and adjusting for covariates (age and sex), only the Vpr G41 and A55 groups was nearing significance for higher levels of QUIN compared to the Vpr S41 and T55 groups, respectively (all p =.023). Multiple regression results revealed that Vpr amino acid variations at position 41 (adj R2 = 0.049, β = 0.505; p =.023), and 55 (adj R2 = 0.126, β = 0.444; p =.023) displayed significant associations with QUIN after adjusting for age and sex. Lastly, the higher QUIN levels observed in the Vpr G41 group were found to be correlated with suPAR (r =.588, p =.005). These results collectively underscore the importance of specific Vpr amino acid substitutions in influencing QUIN and inflammation (specifically suPAR levels), potentially contributing to our understanding of their roles in the pathogenesis and
neuropathogenesis of HIV-1.