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...