Activation of caspases and p53 by bovine herpesvirus 1 infection results in programmed cell death and efficient virus release

Programmed cell death (PCD), or apoptosis, is initiated in response to vari ous stimuli, including virus infection. Bovine herpesvirus 1 (BHV-1) induce s PCD in peripheral blood mononuclear cells at the G(0)/G(1) phase of the c ell cycle (E. Hanon, S. Hoornaert, F. Dequiedt, A. Vanderplasschen, J. Lyak u, L. Willems, and P.-P. Pastoret, Virology 232:351-358, 1997). However, pe netration of virus particles is not required for PCD (E. Hanon, G. Meyer, A . Vanderplasschen, C. Dessy-Doize, E. Thiry, and P. P. Pastoret, J. Virol, 72:7638-7641, 1998). The mechanism by which BHV-1 induces PCD in peripheral blood mononuclear cells is not understood, nor is it clear whether nonlymp hoid cells undergo PCD following infection. This study demonstrates that in fection of bovine kidney (MDBK) cells with BHV-1 leads to PCD, as judged by terminal deoxynucleotidyltransferase mediated dUTP-biotin nick end labelin g, DNA laddering, and chromatin condensation. p53 ap pears to be important in this process, because p53 levels and promoter activity increased after i nfection. Expression of proteins that are stimulated by p53 (p21(WafI) and Bar) is also activated after infection. Cleavage of Bcl-x(L) a protein that inhibits PCD, occurred after infection, suggesting that caspases (interleu kin-1 beta-converting enzyme-like proteases) were activated. Other caspase substrates [poly(ADP-ribose) polymerase and actin] are also cleaved during the late stages of infection. Inhibition of caspase activity delayed cytoto xic activity and virus release but increased the overall virus yield. Taken together, these results indicate that nonlymphoid cells undergo PCD near t he end of productive infection and further suggest that caspases enhance vi rus release.