Northwestern University Feinberg School of Medicine, Department of Pediatrics, Division of Pediatric Infectious Diseases, Department of Medicine, Division of Adult Infectious Diseases, Chicago, Illinois 60611, USA.
Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Division of Biostatistics, Chicago, Illinois 60611, USA.
J Clin Endocrinol Metab. 2022 Jan 1;107(1):119-135. doi: 10.1210/clinem/dgab663.
Disentangling contributions of HIV from antiretroviral therapy (ART) and understanding the effects of different ART on metabolic complications in persons living with HIV (PLHIV) has been challenging.
We assessed the effect of untreated HIV infection as well as different antiretroviral therapy (ART) on the metabolome/lipidome.
Widely targeted plasma metabolomic and lipidomic profiling was performed on HIV-seronegative individuals and people living with HIV (PLHIV) before and after initiating ART (tenofovir/emtricitabine plus atazanavir/ritonavir [ATV/r] or darunavir/ritonavir [DRV/r] or raltegravir [RAL]). Orthogonal partial least squares discriminant analysis was used to assess metabolites/lipid subspecies that discriminated between groups. Graphical lasso estimated group-specific metabolite/lipid subspecies networks associated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Correlations between inflammatory markers and metabolites/lipid subspecies were visualized using heat maps.
Of 435 participants, 218 were PLHIV. Compared to HIV-seronegative individuals, ART-naive PLHIV exhibited higher levels of saturated triacylglycerols/triglycerides (TAGs) and 3-hydroxy-kynurenine, lower levels of unsaturated TAGs and N-acetyl-tryptophan, and a sparser and less heterogeneous network of metabolites/lipid subspecies associated with HOMA-IR. PLHIV on RAL vs ATV/r or DRV/r had lower saturated and unsaturated TAGs. Positive correlations were found between medium-long chain acylcarnitines (C14-C6 ACs), palmitate, and HOMA-IR for RAL but not ATV/r or DRV/r. Stronger correlations were seen for TAGs with interleukin 6 and high-sensitivity C-reactive protein after RAL vs ATV/r or DRV/r initiation; these correlations were absent in ART-naive PLHIV.
Alterations in the metabolome/lipidome suggest increased lipogenesis for ART-naive PLHIV vs HIV-seronegative individuals, increased TAG turnover for RAL vs ATV/r or DRV/r, and increased inflammation associated with this altered metabolome/lipidome after initiating ART. Future studies are needed to understand cardiometabolic consequences of lipogenesis and inflammation in PLHIV.
阐明 HIV 感染与抗逆转录病毒治疗（ART）的作用，并了解不同 ART 对 HIV 感染者（PLHIV）代谢并发症的影响一直具有挑战性。
我们评估了未经治疗的 HIV 感染以及不同抗逆转录病毒治疗（ART）对代谢组/脂质组的影响。
对 HIV 阴性个体和 PLHIV 在开始 ART（替诺福韦/恩曲他滨加阿扎那韦/利托那韦[ATV/r]或达芦那韦/利托那韦[DRV/r]或拉替拉韦[RAL]）前后进行了广泛靶向的血浆代谢组学和脂质组学分析。正交偏最小二乘判别分析用于评估可区分组别的代谢物/脂质亚类。图形套索估计与稳态模型评估的胰岛素抵抗（HOMA-IR）相关的特定于组的代谢物/脂质亚类网络。使用热图可视化炎症标志物与代谢物/脂质亚类之间的相关性。
在 435 名参与者中，有 218 名是 PLHIV。与 HIV 阴性个体相比，未经 ART 治疗的 PLHIV 表现出更高水平的饱和三酰甘油/甘油三酯（TAGs）和 3-羟基犬尿氨酸，更低水平的不饱和 TAGs 和 N-乙酰色氨酸，以及与 HOMA-IR 相关的代谢物/脂质亚类的稀疏且异质性更小的网络。与 ATV/r 或 DRV/r 相比，RAL 治疗的 PLHIV 的饱和和不饱和 TAGs 水平更低。在 RAL 中发现中等长链酰基辅酶 A（C14-C6 ACs）、棕榈酸和 HOMA-IR 之间存在正相关，但在 ATV/r 或 DRV/r 中则不存在。在开始 RAL 后，与 IL-6 和高敏 C 反应蛋白相比，TAGs 显示出更强的相关性；在开始 ART 之前，PLHIV 中不存在这种相关性。
代谢组/脂质组的改变表明未经治疗的 PLHIV 与 HIV 阴性个体相比，脂肪生成增加，RAL 与 ATV/r 或 DRV/r 相比，TAG 周转率增加，并且在开始 ART 后，这种改变的代谢组/脂质组与炎症相关。需要进一步的研究来了解 PLHIV 中脂肪生成和炎症的代谢后果。
