Gain of Virulence Caused by Loss of a Gene in Murine Cytomegalovirus

Abstract

ABSTRACT Mouse strains are either resistant or susceptible to murine cytomegalovirus (MCMV). Resistance is determined by the Cmv1 r ( Ly49h ) gene, which encodes the Ly49H NK cell activation receptor. The protein encoded by the m157 gene of MCMV has been defined as a ligand for Ly49H. To find out whether the m157 protein is the only Ly49H ligand encoded by MCMV, we constructed the m157 deletion mutant and a revertant virus. Viruses were tested for susceptibility to NK cell control in Ly49H + and Ly49H − mouse strains. Deletion of the m157 gene abolished the viral activation of Ly49H + NK cells, resulting in higher virus virulence in vivo. Thus, in the absence of m157 , Ly49H + mice react like susceptible strains. 129/SvJ mice lack the Ly49H activation NK cell receptor but express the inhibitory Ly49I NK cell receptor that binds to the m157 protein. The Δ m157 inhibitory phenotype was weak because MCMV encodes a number of proteins that mediate NK inhibition, whose contribution could be shown by another mutant.