第一型單純疱疹病毒 (herpes simplex virus 1) 感染世界上大多數的人口。此病毒能夠引發致死性的腦炎，並且在給予抗病毒藥物的前提下，仍然能夠有很高的致死率。目前第一線臨床用藥為acyclovir及其衍生物，然而免疫缺失的病人長期服藥使得單純疱疹病毒在病人體內突變成具抗藥性的病毒株。基於以上原因，我們需要研發新的藥物及治療方法來對抗第一型單純疱疹病毒感染。先前有文獻指出，疱疹病毒感染細胞時除了利用本身的蛋白質幫助自身感染以外，也會利用宿主細胞中的分子來幫助病毒感染、複製與傳播。其中，蛋白激素酶B (Akt) 便是第一型單純疱疹病毒的目標之一。病毒會在感染時活化細胞中的Akt，借此幫助病毒感染、散播以及潛伏。本篇我們主要探討Akt抑制劑，miltefosine，對於第一型單純疱疹病毒感染的功效。根據我們的細胞研究結果顯示，第一型單純疱疹病毒感染細胞後確實能夠促進細胞Akt活化，給予感染細胞miltefosine能夠降低細胞內Akt活化 (p-Akt)，並且能夠有效降低感染細胞內的病毒量。除此之外，我們的研究結果也顯示miltefosine抑制病毒複製的機制與interferon β無關，可能與miltefosine降低細胞內活化NF-κB有關。在動物實驗中，miltefosine也能有效降低感染野生型或是具抗藥性病毒感染小鼠體內的病毒量，並稍微提升感染小鼠存活率。總和以上實驗結果，我們發現了miltefosine作為抗病毒藥物的潛力。

Herpes simplex virus 1 (HSV-1) infects the majority of human population worldwide. HSV-1 can induce fatal encephalitis (HSE) with a high incidence compared to other viruses. Acyclovir and related nucleoside analogues are used to treat patients, but the mortality of treated patients remains high. More therapies are needed. During infection, HSV-1 interacts with cellular factors, which can modulate viral infection to affect the severity of virus-induced diseases. Previous studies showed that HSV-1 can activate phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) axis to enhance virus entry, viral nucleocapsid transportation, and protein translation. Furthermore, Akt can reduce type I interferon production by inhibiting cGAS activation through phosphorylation of cGAS. Here, we study the effect of suppressing Akt phosphorylation on HSV-1 infection. Our results showed that suppression of Akt phosphorylation by the inhibitor, miltefosine reduced viral replication in cells and mice. Moreover, miltefosine slightly improved the survival rates of mice infected with HSV-1. To our surprise, the levels of interferon β in infected mice and cells treated with saline or with miltefosine were comparable, suggesting that miltefosine fails to promote the cGAS/STING pathway in HSV-1 infection. In conclusion, our results show the potential of miltefosine as an anti-HSV-1 treatment.

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