Glutamine supplementation suppresses herpes simplex virus reactivation III

Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection. RNA from HSV-1 latently infected trigeminal ganglia of mice receiving dietary supplement of glutamine (test) were compared to those that received supplemental glycine (control); 9 arrays for each condition including 1 technical replicate. Each independent RNA sample was composed of 4 Tg organs from two mice pooled.

慢性病毒感染的临床治疗颇具难度，亟需开发新型治疗策略，尤其是能够增强机体免疫应答的方案。单纯疱疹病毒（Herpes simplex virus, HSV）可建立潜伏感染，且复发频率较高；即便接受抑制性抗病毒治疗，仍可能出现突破性病毒复发。病毒特异性T细胞在控制HSV感染中发挥关键作用，而活化T细胞的增殖过程依赖谷氨酰胺代谢的增强。本研究发现，对潜伏感染HSV-1的小鼠以及感染HSV-2的豚鼠给予口服谷氨酰胺补充剂，可降低病毒的复发激活率。对谷氨酰胺处理小鼠的转录组分析结果显示，多种干扰素（Interferon, IFN）-γ诱导基因的表达水平显著上调。与野生型小鼠不同，在干扰素-γ敲除小鼠中，补充谷氨酰胺无法有效降低HSV-1的复发激活速率。经谷氨酰胺处理的小鼠，其潜伏感染的神经节内，分泌IFN-γ的HSV特异性CD8阳性T细胞数量显著升高。综上，谷氨酰胺或可通过增强IFN-γ相关的免疫应答，降低潜伏病毒感染的复发激活速率。本研究将补充膳食谷氨酰胺的实验组小鼠潜伏感染HSV-1的三叉神经节（trigeminal ganglia, Tg）RNA，与补充甘氨酸的对照组小鼠样本进行对比；每组设置9个基因芯片样本，包含1个技术重复。每份独立RNA样本均由2只小鼠的4个三叉神经节器官混合制备而成。