背景:HIV-1具有完善的机制来破坏HIV感染者的基本途径,如炎症和新陈代谢。此外,包括Tat和Vif在内的基本HIV-1蛋白中氨基酸序列的多样性,与这些途径的失调有关,并随后影响HIV感染者的临床结局。然而,Tat和Vif氨基酸序列变异与色氨酸-犬尿氨酸(Trp-Kyn)途径的特异性免疫标记和代谢产物之间的关系尚不清楚。因此,本研究旨在探讨Tat/Vif氨基酸序列多样性与Trp-Kyn代谢产物(喹啉酸(QUIN),Trp,犬尿氨酸(KA),Kyn和Trp/Kyn比率),以及特异性免疫标志物(sCD163、suPAR、IL-6,NGAL和hsCRP)在n=67例南非cART初治HIV感染者中。
方法:Sanger测序用于确定血液来源的Tat/Vif氨基酸序列多样性。为了测量Trp-Kyn代谢物,使用靶向方法采用LC-MS/MS代谢组学平台.为了测量免疫标志物,使用酶联免疫吸附测定和颗粒增强比浊法。
结果:调整协变量后,sCD163(p=0.042)和KA(p=0.031)在Tat签名N24和R57的参与者中分别较高,Tat的第24位(adjR2=0.048,β=-0.416,p=0.042)和57位(adjR2=0.166,β=0.535,p=0.031)的氨基酸变异与sCD163和KA相关,分别。
结论:这些初步发现表明,Tat中的氨基酸变异可能对潜在的致病性HIV-1机制有影响,因此,这项工作值得进一步调查。
BACKGROUND: HIV-1 has well-established mechanisms to disrupt essential pathways in people with HIV, such as inflammation and metabolism. Moreover, diversity of the amino acid sequences in fundamental HIV-1 proteins including Tat and Vif, have been linked to dysregulating these pathways, and subsequently influencing clinical outcomes in people with HIV. However, the relationship between Tat and Vif amino acid sequence variation and specific immune markers and metabolites of the tryptophan-kynurenine (Trp-Kyn) pathway remains unclear. Therefore, this study aimed to investigate the relationship between Tat/Vif amino acid sequence diversity and Trp-Kyn metabolites (quinolinic acid (QUIN), Trp, kynurenic acid (KA), Kyn and Trp/Kyn ratio), as well as specific immune markers (sCD163, suPAR, IL-6, NGAL and hsCRP) in n = 67 South African cART-naïve people with HIV.
METHODS: Sanger sequencing was used to determine blood-derived Tat/Vif amino acid sequence diversity. To measure Trp-Kyn metabolites, a LC-MS/MS metabolomics platform was employed using a targeted approach. To measure immune markers, Enzyme-linked immunosorbent assays and the Particle-enhanced turbidimetric assay was used.
RESULTS: After adjusting for covariates, sCD163 (p = 0.042) and KA (p = 0.031) were higher in participants with Tat signatures N24 and R57, respectively, and amino acid variation at position 24 (adj R2 = 0.048, β = -0.416, p = 0.042) and 57 (adj R2 = 0.166, β = 0.535, p = 0.031) of Tat were associated with sCD163 and KA, respectively.
CONCLUSIONS: These preliminary findings suggest that amino acid variation in Tat may have an influence on underlying pathogenic HIV-1 mechanisms and therefore, this line of work merits further investigation.