Bovine viral diarrhea virus 2 strains generate deletion viral genomes primarily in the NS2 region of the viral genome

Authors: Holthausen, David; Bayles, Darrell; NEILL, JOHN - Retired ARS Employee; Dassanayake, Rohana; FALKENBERG, SHOLLIE - Former ARS Employee; Nielsen, Daniel; Zakrzewicz, Anna; MENGHWAR, HARISH - Oak Ridge Institute For Science And Education (ORISE); Casas, Eduardo

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/8/2025
Publication Date: 9/24/2025
Citation: Holthausen, D.J., Bayles, D.O., Neill, J.D., Dassanayake, R.P., Falkenberg, S.M., Nielsen, D.W., Goldkamp, A.K., Menghwar, H., Casas, E. 2025. Bovine viral diarrhea virus 2 strains generate deletion viral genomes primarily in the NS2 region of the viral genome. Frontiers in Veterinary Science. https://doi.org/10.3389/fvets.2025.1686098.
DOI: https://doi.org/10.3389/fvets.2025.1686098

Interpretive Summary: Bovine viral diarrhea virus (BVDV) is a major concern for cattle producers. BVDV infection of pregnant cows can cross the placenta to the fetus and cause loss of the pregnancy or persistent infection of the calf, if their immune system has not yet matured. These persistently infected calves are a major source of BVDV transmission within the herd. We recently reported that BVDV1, one of the two major types of BVDV, produces genomes with internal deletions that cannot replicate as part of their normal life cycle. These genomes help the virus by regulating its reproduction in the host, and helping the virus persist by reducing host signals to kill infected cells. Hotspots for these deletion regions are targets of interest for understanding the interaction of the virus with the host and the development of new antivirals and vaccines. In this study we determined the presence of deletion viral genomes by BVDV2 strains and characterized similarities and differences among subtypes BVDV2a, BVDV2b, and BVDV2c. 90% of the deletion viral genomes produced by BVDV2 strains delete a region that codes for one of the nonstructural proteins, NS2. BVDV2c strains generated one hundred fifty times as many deletion viral genomes in comparison to BVDV2a strains.

Technical Abstract: Bovine viral diarrhea virus (BVDV) is a virus of economic concern for the cattle industry worldwide. Transplacental BVDV infection during pregnancy, before sufficient maturation of the fetal immune system, results in significant reproductive losses via spontaneous abortion and the generation of offspring that are persistently infected and immunotolerant to the infected noncytopathic BVDV strain. These persistently infected animals act as reservoirs and are the major source of BVDV transmission within the herd. Previously, we reported bioinformatic analyses showing that BVDV1a and 1b genotypes generate distinct sets of diverse deletion viral genomes (DelVGs) during the natural viral life cycle. Deletion viral genomes are generated by skipping events that occur during genome synthesis by the error-prone viral replication machinery. These replication deficient genomes play many roles in host-pathogen interactions, including being implicated in the establishment of viral persistence. Here, we analyzed twenty-one field isolates of the BVDV2 genotype for the presence and characterization of DelVGs using Illumina MiSeq BVDV2 genome sequencing reads. BVDV2 strains generate significantly more NS2 DelVGs than any other region of the genome, with over 90% of those deletions having both 5' and 3' junctions in the NS2 region of the genome. BVDV2c strains produce approximately one hundred fifty times as many DelVG reads as BVDV2a strains. Of the BVDV2a isolates queried, cytopathic BVDV2a strains generated twice as many NS2 DelVG reads as compared to noncytopathic BVDV2a strains.