High genomic stability of Andes virus following successive passage <i>in vivo</i> in Syrian hamsters

Andes virus (ANDV) is a South American hantavirus that causes hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory infection with a case fatality rate as high as 40%. A critical model for studying HCPS is the Syrian hamster model, which faithfully recapitulates key aspects of the disease. Recent studies have shown that strains of ANDV from different origins, i.e., from rodent or human hosts, can produce widely different outcomes in the hamster model. CHI-7913, a human isolate, does not cause lethal disease and replicates poorly in hamster tissues compared with the classical rodent isolate Chile-9717869. Here, we passaged CHI-7913 <i>in vivo</i> in Syrian hamsters 25 times and infected groups of hamsters with virus from passages 2, 12, and 24 to assess whether viral adaptation occurs that might ultimately drive the phenotype of the virus during infection in this model. Very few mutations occurred during passage in hamsters, with only a single coding mutation discovered after 25 passages. Nearly all mutations occurring in hamsters occurred early, within two passages, and none of the passaged virus caused overt disease or pathology in infected hamsters, consistent with minimal changes in the viral genome. Early in infection, CHI-7913 viral RNA levels were still well below those seen in lethal Chile-9717869 infection. Overall, our data offer insights into the lack of selective pressure on hantaviruses in certain hosts and further evidence of distinct outcomes between rodent and human-derived viral isolates that should be studied further in additional viral species.IMPORTANCEInfection of Syrian hamsters with Andes virus (ANDV) can result in disparate outcomes, depending on the source of the virus used for the infection. The ANDV strain CHI-7913 does not cause lethal disease in hamsters but is able to replicate in hamster tissues. We successively passaged CHI-7913 <i>in vivo</i> to study how continued infection influences adaptation in hamsters and whether passaging would lead to the development of a lethal model, as sometimes occurs with other viruses. Surprisingly, even after 25 passages, minimal mutations occurred in ANDV CHI-7913 genomes, with only one coding mutation present above consensus by passage 25, in the viral glycoprotein. Our data suggest that depending on both viral origin and the host, hantaviruses may face minimal selective pressure to mutate toward a disease phenotype. Studies with additional ANDV strains and other hantavirus species are warranted to further study this phenomenon.