Herpes Simplex Virus Inhibits Apoptosis through the Action of Two Genes, Us5 and Us3

Apoptosis of virus-infected cells occurs either as a direct response to viral infection or upon recognition of infection by the host immune response. Apoptosis reduces production of new virus from these cells, and therefore viruses have evolved inhibitory mechanisms. We previously showed that laboratory strains of herpes simplex virus type 1 (HSV-1) protect infected cells from apoptosis induced by cytotoxic T lymphocytes or ethanol. We have now evaluated the ability of HSV-1 and HSV-2 laboratory and clinical isolates to inhibit apoptosis induced by anti-Fas antibody or UV irradiation and explored the genetic basis for this inhibition. HSV-1 isolates inhibited apoptosis induced by UV or anti-Fas antibody. In contrast, HSV-2 clinical isolates failed to inhibit apoptosis induced by either stimulus, although the HSV-2 laboratory strain 333 had a partial inhibitory effect on UV-induced apoptosis. Inhibition of apoptosis by HSV was accompanied by marked reduction of caspase-3 and caspase-8 activity. Deletion of the HSV-1 Us3 gene markedly reduced inhibition of UV-induced apoptosis and partially abrogated inhibition of Fas-mediated apoptosis. Conversely, deletion of the HSV-1 Us5 gene markedly reduced protection from Fas-mediated apoptosis and partially abrogated protection from UV. The Us11 and Us12 genes were not necessary for protection from apoptosis induced by either stimulus. The differences between HSV-1 and HSV-2 in the ability to inhibit apoptosis may be factors in the immunobiology of HSV infections.

病毒感染细胞的细胞凋亡（apoptosis）既可作为病毒感染的直接应答发生，亦可在宿主免疫应答识别感染事件后触发。细胞凋亡可减少受感染细胞内新生病毒的产出，因此病毒已进化出对应的抑制机制。我们先前的研究证实，实验室培养的单纯疱疹病毒1型（herpes simplex virus type 1, HSV-1）可保护受感染细胞免受细胞毒性T淋巴细胞（cytotoxic T lymphocytes）或乙醇诱导的细胞凋亡。本研究中，我们评估了HSV-1与单纯疱疹病毒2型（herpes simplex virus type 2, HSV-2）的实验室株及临床分离株（clinical isolates）抑制抗Fas抗体（anti-Fas antibody）或紫外线照射（UV irradiation）诱导的细胞凋亡的能力，并探究了该抑制作用的遗传基础（genetic basis）。实验结果显示，HSV-1分离株可有效抑制紫外线或抗Fas抗体诱导的细胞凋亡。与之形成鲜明对比的是，HSV-2临床分离株无法抑制任一刺激物诱导的细胞凋亡；尽管HSV-2实验室株333对紫外线诱导的细胞凋亡仅具备部分抑制效果。HSV对细胞凋亡的抑制作用伴随半胱天冬氨酸蛋白酶3（caspase-3）与半胱天冬氨酸蛋白酶8（caspase-8）活性的显著降低。敲除HSV-1的Us3基因可显著削弱其对紫外线诱导的细胞凋亡的抑制能力，并部分取消其对Fas介导的细胞凋亡的抑制作用。反之，敲除HSV-1的Us5基因可显著降低其对Fas介导的细胞凋亡的保护效应，并部分取消其对紫外线诱导凋亡的保护能力。Us11与Us12基因对于任一刺激物诱导的细胞凋亡的保护作用均非必需。HSV-1与HSV-2在抑制细胞凋亡能力上的差异，或可成为影响单纯疱疹病毒感染免疫生物学（immunobiology）进程的相关因素。