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Cytomegaloviruses encode numerous products that inhibit antigen presentation in the MHC class I pathway in vitro. The mouse cytomegalovirus (MCMV) glycoprotein gp40, encoded by the m152 gene retains murine MHC class I complexes in the ERGIC/cis-Golgi compartment (Ziegler et al., Immunity 6:57, 1997). To investigate the in vivo significance of this gene function during MCMV infection of the natural host, we constructed recombinants of MCMV in which the m152 gene was deleted, as well as the corresponding virus revertants. Deletion of the m152 gene has no effect on virus replication in cell culture, whereas after infection of mice the m152 deficient virus replicates to significantly lower virus titers. This attenuating effect is lifted by reinsertion of the gene into the mutant. Mutants and revertants grow to the same titer in mice deficient for MHC-class I effector function. These results prove that MHC reactive functions protect cytomegaloviruses against the attack by CD8+ T lymphocytes in vivo (Krmpotić et al., J. Exp. Med. 190:1285, 1999). In addition, the m152 deletion affects virus control by NK cells in vivo. However, contrary to the expected, the deletion of the m152 function, although associates with increased MHC class I expression, renders the virus more sensitive to NK cells. This NK cell sensitizing effect is mouse strain specific. Since infected cells from responder and nonresponder strains are recognized, specificity is defined at the level of the NK cell receptor. In conclusion, we showed for the first time that a herpesvirus protein can downmodulate both the adaptive and the innate immune.

Murine cytomegalovirus (MCMV) glycoprotein (gp40) encoded by the m152 gene blocks export of MHC class I complexes from the ERGIC/cis-Golgi compartment, and thereby prevents the presentation of viral antigens to cytotoxic T lymphocytes (Ziegler H., R. Thale, P. Lučin, W. Muranyi, T. Flohr, H. Hengel, H. Farrell, W. Rawlinson, and U.H. Koszinowski. 1997. Immunity 6:57). A recombinant MCMV strain harboring deletion of the m152 gene and the corresponding revertant virus were constructed to investigate the biological significance of this gene product in vivo. Recombinant viruses were selected on the basis of lacZ and/or gpt gene expression and marker genes were subsequently deleted using the cre-loxP recombination system. Deletion of the m152 gene had no effect on virus growth in primary and NIH 3T3 fibroblasts cell culture. The m152 deletion mutant virus replicated to lower titers and exhibited an attenuated disease course in vivo. Depletion studies demonstrated that the absence of m152 gene product renders the virus more sensitive to control by T cells during infection, thus confirming the putative role of this gene product in immunoevasion. In further support of the role of the m152 gene product in evasion of host T-dependent control mechanisms, we report that the deletion mutant and revertant virus strain replicated to similar titers in CD8-knockout mice and in mice deficient of MHC class I molecules. Adoptive transfer studies of naive T lymphocytes also indicated that absence of m152 gene function sensitizes the virus to the primary immune response. Altogether, the results demonstrated that expression of a single viral glycoprotein that interferes with the process of antigen presentation in contex of MHC class I pathway strongly modulates the function of T lymphocytes in vivo.