Wattre P, Bert V, Hober D
Laboratoire de virologie, bâtiment IRFPPS, CHRU, Lille, France.
Ann Biol Clin (Paris). 1996;54(5):189-97.
Homeostasis of cell numbers in tissues is maintained by a critical balance between cell proliferation and programmed cell death or apoptosis. Many human viruses are able to develop suitable strategies for modifying apoptosis in virus-infected cells and in virus-primed T cells. Apoptosis is characterized by the fragmentation of nuclear DNA into 180-200 bp apoptotic bodies and can be analysed microscopically or by flow cytometry using staining with various dyes. Moreover DNA cleavage can be identified by electrophoresis and by specific labeling using in situ nucleotidyltransferase assay (ISNT), terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling technique (Tunel), or by Elisa. Adenovirus E1A induces expression of protooncogenes c-myc and c-fos which sensitize cells to apoptosis; EBV EBNA-5, and adenovirus E1A, HPV E7, and polyomavirus large T act in the same way by displacing pRB-bound E2F. EBV EBNA-5, HPV E6, Adenovirus E1B 55 kDa inactivate the tumor suppressor protein p53 and engage the cells in the transformation process. EBV LMP-1, HHV6, and HTLV1 tax induce the antiapoptotic bcl-2 protein. EBV BHRF1 encodes proteins with homology to bcl-2 and Adenovirus E1B 19 kDa encodes proteins that have protective functions similar to bcl-2. Activated lymphocytes responding to viral infections express high levels of fas and are susceptible to apoptosis. TNF alpha can down- or up-regulate fas and down-regulates TNF-R. Adenovirus E1B 19 kDa blocks the proapoptotic activity of TNF alpha. Inversly, Cytomegalovirus, hepatitis C virus and Myxoviruses up-regulate fas antigen prior to undergoing apoptosis. In HIV-infected patients, CD4+ T-cell apoptosis is mediated by the cytopathic effect of the virus and the cell surface expression of gp 120-env protein. Moreover, an accelerated T-cell apoptosis in HIV-infected individuals is characterized by (i) HIV gp120-CD4+ cross-linking and subsequent aberrant signaling of T-cells, (ii) involvement of TNF alpha-fas/Apo-1 (TNF-R) binding, (iii) involvement of accessory cells as an apoptosis inducer and as a result of defective antigen presentation, (iv) possible superantigen activity induced by HIV products and cofactors. Many viruses also encode proteins with protease activity which could induce apoptosis. The induction of apoptosis may result in virus clearance, in contrast the inhibition of apoptosis may result in virus cell transformation and viral persistence. Indirectly, the apoptosis of infected cells may be induced by CTLs, NK cells and cytokines. In addition, apoptosis-mediated physiological depletion of T lymphocytes in the course of viral infection can silence the immune response and can induce immunodeficiency.
组织中细胞数量的稳态是通过细胞增殖与程序性细胞死亡或凋亡之间的关键平衡来维持的。许多人类病毒能够制定合适的策略来改变病毒感染细胞和病毒致敏T细胞中的凋亡。凋亡的特征是核DNA断裂成180 - 200 bp的凋亡小体，可以通过显微镜分析或使用各种染料染色的流式细胞术进行分析。此外，DNA切割可以通过电泳以及使用原位核苷酸转移酶测定（ISNT）、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记技术（Tunel）或酶联免疫吸附测定（ELISA）进行特异性标记来鉴定。腺病毒E1A诱导原癌基因c-myc和c-fos的表达，使细胞对凋亡敏感；EB病毒EBNA-5、腺病毒E1A、人乳头瘤病毒E7和多瘤病毒大T抗原以相同方式通过取代与pRB结合的E2F发挥作用。EB病毒EBNA-5、人乳头瘤病毒E6、腺病毒E1B 55 kDa使肿瘤抑制蛋白p53失活，并使细胞参与转化过程。EB病毒LMP-1、人疱疹病毒6型和人类嗜T淋巴细胞病毒1型tax诱导抗凋亡蛋白bcl-2。EB病毒BHRF1编码与bcl-2具有同源性的蛋白质，腺病毒E1B 19 kDa编码具有与bcl-2相似保护功能的蛋白质。对病毒感染作出反应的活化淋巴细胞表达高水平的fas，并且易发生凋亡。肿瘤坏死因子α（TNFα）可以下调或上调fas，并下调TNF-R。腺病毒E1B 19 kDa阻断TNFα的促凋亡活性。相反，巨细胞病毒、丙型肝炎病毒和黏液病毒在发生凋亡之前上调fas抗原。在HIV感染患者中，CD4 + T细胞凋亡是由病毒的细胞病变效应和gp 120-env蛋白的细胞表面表达介导的。此外，HIV感染个体中加速的T细胞凋亡的特征在于：（i）HIV gp120-CD4 +交联以及随后T细胞的异常信号传导；（ii）TNFα-fas/Apo-1（TNF-R）结合的参与；（iii）辅助细胞作为凋亡诱导剂的参与以及由于抗原呈递缺陷导致的结果；（iv）HIV产物和辅助因子可能诱导的超抗原活性。许多病毒还编码具有蛋白酶活性的蛋白质，这些蛋白质可能诱导凋亡。凋亡的诱导可能导致病毒清除，相反，凋亡的抑制可能导致病毒细胞转化和病毒持续存在。间接而言，感染细胞的凋亡可能由细胞毒性T淋巴细胞（CTL）、自然杀伤细胞（NK细胞）和细胞因子诱导。此外，病毒感染过程中凋亡介导的T淋巴细胞生理性消耗可使免疫反应沉默并诱导免疫缺陷。
