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RESEARCH PRODUCT

Frequent coinfection of cells explains functional in vivo complementation between cytomegalovirus variants in the multiply infected host.

subject

description

In contrast to many other virus infections, primary cytomegalovirus (CMV) infection does not fully protect against reinfection. Accordingly, clinical data have revealed a coexistence of multiple human CMV variants/ strains in individual patients. Notably, the phenomenon of multiple infection was found to correlate with increased virus load and severity of CMV disease. Although of obvious medical relevance, the mechanism underlying this correlation is unknown. A weak immune response in an individual could be responsible for a more severe disease and for multiple infections. Alternatively, synergistic contributions of variants that differ in their biological properties can lead to qualitative changes in viral fitness by direct interactions such as genetic recombination or functional complementation within coinfected host cells. We have addressed this important question paradigmatically with the murine model by differently designed combinations of two viruses employed for experimental coinfection of mice. Specifically, a murine cytomegalovirus (MCMV) mutant expressing Cre recombinase was combined for coinfection with a mutant carrying Cre-inducible green fluorescent protein gene, and attenuated mutants were combined for coinfection with wild-type virus followed by two-color in situ hybridization studies visualizing the replication of the two viruses in infected host organs. These different approaches concurred in the conclusion that coinfection of host cells is more frequent than statistically predicted and that this coinfection alters virus fitness by functional trans-complementation rather than by genetic recombination. The reported findings make a major contribution to our molecular understanding of enhanced CMV pathogenicity in the multiply infected host. Human cytomegalovirus (HCMV), a betaherpesvirus that is highly prevalent in the population, is currently the most frequent cause of viral congenital infection in the western world and a major cause of morbidity and fatal disease in patients undergoing bone marrow or organ transplantation, as well as in patients suffering from acquired or inborn immunodeficiency. Apparently, primary HCMV infection offers only partial protection against reinfection by a different strain of the virus, as defined by serology and the genotype of variants of the CMV glycoprotein H (6). This implies that multiple CMV strains can accumulate in a person during a lifetime. Genomes of multiple HCMV strains have been found to coexist in the immunodeficient host (12). This important finding has been reported for immunocompetent patients as well (18, 32). Therefore, the coinfection observed in the immunocompromised patient could be caused by simultaneous reactivation of previously acquired multiple strains and not exclusively by reinfections with novel CMV strains upon immunosuppression. The presence of multiple CMV strains/variants during congen