Intrauterine transmission of human cytomegalovirus (HCMV) to the fetus following primary infection in early and late pregnancy usually results in severe neurological handicaps and sensorineural hearing loss with typical migrational anomalies, optic atrophy, disturbed myelination, cerebella hypoplasia, microcephaly, hydrocephaly, and lissencephaly. Recently, evidences raised from the phenotype of p73-deficient mice show that an association may exist between the expression of the TP53 homologous gene and HCMV tropism in the brain, suggesting an implication of p73 in viral persistence. In this study, we demonstrated that HCMV-mediated inhibition of apoptosis only occurs in p73-expressing cells. Upon infection, an accumulation of ⌬N-p73␣ isoforms was observed in HCMV-infected p73-positive cells. This phenomenon was shown to be responsible for the subsequent acquired resistance to apoptosis of infected cells. Inhibition of apoptosis in p73-positive cells by HCMV may thus contribute both to virus persistency and abnormal nervous cell survival. This finding provides the first molecular basis for HCMV-associated abnormal embryonic development and neurological defects in newborns.Human cytomegalovirus (HCMV), 1 a ␤-herpes virus, is harmless to most immunocompetent people. However, HCMV is responsible for serious illness and death in immunocompromised hosts such as AIDS patients, as well as patients receiving immunosuppressive treatment following organ transplantation. Cytomegalovirus infection is the most common congenital viral infection and carries a high risk of long term morbidity and mortality. Intrauterine transmission to the unprotected fetus in early and late pregnancy usually results in death or in severe neurological defects including sensorineural hearing loss, optic atrophy, disturbed myelination, cerebella hypoplasia, microcephaly, hydrocephaly, and lissencephaly (for reviews, see Refs. 1 and 2). How morphological and functional disorders develop is unclear since little is known about mechanisms underlying the pathogenicity of the virus.Apoptosis is an important process participating in the formation of organs and tissues during embryogenesis and in the clearance of abnormal or misfunctioning cells in the body. At any stages of life, interference with this process is predicted to be damaging for organisms. In the mouse developing brain, surprisingly, murine cytomegalovirus (mCMV) was found to induce apoptosis in non-infected cells, whereas a blocking of apoptosis occurred in infected mature neurons (3). Similar results were obtained with human neuroblastoma cells, which become "immortalized" and resistant to cytotoxic stress following HCMV infection (4). As with many other viruses, HCMV has developed strategies to inhibit apoptosis of infected cells, thus escaping from immune clearance, promoting abnormal cell survival, and favoring viral persistence. Some reports discuss possible mechanisms by which HCMV can block apoptosis. HCMV proteins can directly interact with the tumor suppressor p53 and interfere wit...

The discovery of p73, a p53-related protein with various isotypes resulting from different promoter usage or splicing events, provided new insights into regulation of neurogenesis and tumorigenesis. Among p73 isoforms described thus far, TA-truncated molecules (DN) appeared as key proteins according to their antagonistic activity against transcription factor activity of p53 family members. We previously showed that infection by human cytomegalovirus (HCMV) induced drug resistance and altered p53-and p73-dependent apoptosis of infected cells through accumulation of DN-p73A. In accordance with the ability of p53 to induce apoptosis through death receptors, we asked whether p73 activation could compensate for p53 deficiency. We showed that p73 transcriptional activity sensitized cells to apoptosis through death receptors in a caspase-dependent pathway. Expression of the death-inducing signaling complex (DISC) proteins was unchanged, whereas p73 activation through either cisplatin treatment or ectopic overexpression induced up-regulation of Fas transcription and expression at cell surface. According to its ability to flood cells with DN-p73A, HCMV inhibited p73-dependent Fas-mediated apoptosis, gaining an additional trick to favor its survival in the host cell. Owing to the involvement of p53-and p73-dependent death receptor signaling in development of the central nervous system, immune surveillance of neural cells, and sensitivity of tumors to drugs, our previous and present data prompt us to consider stabilization of DN-p73A by HCMV as a possible mechanism in impairment of embryogenesis and in tumorigenesis. (Cancer Res 2005; 65(7): 2787-94)

Z-ajoene is a garlic-derived compound with known anti-tumour properties. This report argues in favour of pro-apoptotic and cell cycle blockage activities of Z-ajoene on various cell lines involving activation of the p53-family gene products, p53, p63 and p73, at indicated doses. According to its known anti-proteasome activity, Z-ajoene induced a downregulation of MHC-class I expression at the surface of treated cells but did not impair their recognition by CD8+ T cells. We further demonstrated a new activity of Z-ajoene against human cytomegalovirus spreading in vitro that was mediated by an increased number of apoptotic cells after infection. Altogether our data point at the ubiquitous efficiency of Z-ajoene as a new compound to fight against cancers of various origins including those that put up viruses.