The genesis for this special issue on pestiviruses was a joint meeting on pestiviruses organized by the US BVDV Symposia Committee and the European Society for Veterinary Virology that was held October 14 and 15, 2014 in Kansas City, MO. The theme of the meeting was “Pestiviruses: Old enemies and new challenges”. The impetus for this joint effort was the recognition that regional approaches to disease control are at odds with the worldwide traffic in animal products and biologics. Further, the control of newly recognized pestiviruses, such as HoBi-like viruses, is more effective when approached as a global challenge rather than any one nation's problem. The joint meeting featured talks by researchers from North America, South America, Australia and Europe. The papers in this issue arose from keynote talks presented at the joint meeting and are organized around the following themes; pestiviruses and the immune system, genetic variability, the emergence of new pestiviruses and pestivirus control programs.

Bovine viral diarrhea virus (BVDV) has long been associated with a wide variety of clinical syndromes and immune dysregulation, many which result in secondary bacterial infections. Current understanding of immune cell interactions that result in activation and tolerance are explored in light of BVDV infection including: depletion of lymphocytes, effects on neutrophils, natural killer cells, and the role of receptors and cytokines. In addition, we review some new information on the effect of BVDV on immune development in the fetal liver, the role of resident macrophages, and greater implications for persistent infection.

Infection of pregnant cows with noncytopathic (ncp) bovine viral diarrhea virus (BVDV) induces rapid innate and adaptive immune responses, resulting in clearance of the virus in less than 3 weeks. Seven to 14 days after inoculation of the cow, ncpBVDV crosses the placenta and induces a fetal viremia. Establishment of persistent infection with ncpBVDV in the fetus has been attributed to the inability to mount an immune response before 90–150 days of gestational age. The result is ‘immune tolerance’, persistent viral replication and shedding of ncpBVDV. In contrast, we describe the chronic upregulation of fetal Type I interferon (IFN) pathway genes and the induction of IFN-γ pathways in fetuses of cows infected on day 75 of gestation. Persistently infected (PI) fetal IFN-γ concentrations also increased at day 97 at the peak of fetal viremia and IFN-γ mRNA was significantly elevated in fetal thymus, liver and spleen 14–22 days post maternal inoculation. PI fetuses respond to ncpBVDV infection through induction of Type I IFN and IFN-γ activated genes leading to a reduction in ncpBVDV titer. We hypothesize that fetal infection with BVDV persists because of impaired induction of IFN-γ in the face of activated Type I IFN responses. Clarification of the mechanisms involved in the IFN-associated pathways during BVDV fetal infection may lead to better detection methods, antiviral compounds and selection of genetically resistant breeding animals.

The control and prevention of bovine viral diarrhea virus (BVDV) infections has provided substantial challenges. Viral genetic variation, persistent infections, and viral tropism for immune cells have complicated disease control strategies. Vaccination has, however, provided an effective tool to prevent acute systemic infections and increase reproductive efficiency through fetal protection. There has been substantial controversy about the safety and efficacy of BVDV vaccines, especially when comparing killed versus modified-live viral (MLV) vaccines. Furthermore, numerous vaccination protocols have been proposed to protect the fetus and ensure maternal antibody transfer to the calf. These issues have been further complicated by reports of immune suppression during natural infections and following vaccination. While killed BVDV vaccines provide the greatest safety, their limited immunogenicity makes multiple vaccinations necessary. In contrast, MLV BVDV vaccines induce a broader range of immune responses with a longer duration of immunity, but require strategic vaccination to minimize potential risks. Vaccination strategies for breeding females and young calves, in the face of maternal antibody, are discussed. With intranasal vaccination of young calves it is possible to avoid maternal antibody interference and induce immune memory that persists for 6–8 months. Thus, with an integrated vaccination protocol for both breeding cows and calves it is possible to maximize disease protection while minimizing vaccine risks.

Classical swine fever is a highly contagious disease that affects domestic and wild pigs worldwide. The causative agent of the disease is Classical swine fever virus (CSFV), which belongs to the genus Pestivirus within the family Flaviviridae. On the genome level, CSFV can be divided into three genotypes with three to four sub-genotypes. Those genotypes can be assigned to distinct geographical regions. Knowledge about CSFV diversity and distribution is important for the understanding of disease dynamics and evolution, and can thus help to design optimized control strategies. For this reason, the geographical pattern of CSFV diversity and distribution are outlined in the presented review. Moreover, current knowledge with regard to genetic virulence markers or determinants and the role of the quasispecies composition is discussed.

Bovine viral diarrhea viruses (BVDV) are diverse genetically and antigenically. This diversity impacts both diagnostic testing and vaccination. In North America, there are two BVDV species, 1 and 2 with 3 subgentoypes, BVDV1a, BVDV1b and BVDV2a. Initially, US vaccines contained BVDV1a cytopathic strains. With the reporting of BVDV2 severe disease in Canada and the USA there was focus on protection by BVDV1a vaccines on BVDV2 disease. There was also emphasis of controlling persistently infected (PI) cattle resulted in studies for fetal protection afforded by BVDV1a vaccines. Initially, studies indicated that some BVDV1a vaccines gave less than 100% protection against BVDV2 challenge for fetal infection. Eventually vaccines in North America added BVDV2a to modified live virus (MLV) and killed BVDV1a vaccines. Ideally, vaccines should stimulate complete immunity providing 100% protection against disease, viremias, shedding, and 100% fetal protection in vaccinates when challenged with a range of diverse antigenic viruses (subgenotypes). There should be a long duration of immunity stimulated by vaccines, especially for fetal protection. MLV vaccines should be safe when given according to the label and free of other pathogens. While vaccines have now included BVDV1a and BVDV2a, with the discovery of the predominate subgenotype of BVDV in the USA to be BVDV1b, approximately 75% or greater in prevalence, protection in acute challenge and fetal protection studies became more apparent for BVDV1b. Thus many published studies examined protection by BVDV1a and BVDV2a vaccines against BVDV1b in acute challenge and fetal protection studies. There are no current BVDV1b vaccines in the USA. There are now more regulations on BVDV reproductive effects by the USDA Center for Veterinary Biologics (CVB) regarding label claims for protection against abortion, PI calves, and fetal infections, including expectations for studies regarding those claims. Also, the USDA CVB has a memorandum providing the guidance for exemption of the warning label statement against the use of the MLV BVDV in pregnant cows and calves nursing pregnant cows. In reviews of published studies in the USA, the results of acute challenge and fetal protection studies are described, including subgenotypes in vaccines and challenge strains and the results in vaccinates and the vaccinates' fetuses/newborns. In general, vaccines provide protection against heterologous strains, ranging from 100% to partial but statistically significant protection. In recent studies, the duration of immunity afforded by vaccines was investigated and reported. Issues of contamination remain, especially since fetal bovine serums may be contaminated with noncytopathic BVDV. In addition, the potential for immunosuppression by MLV vaccines exists, and new vaccines will be assessed in the future to prove those MLV components are not immunosuppressive by experimental studies. As new subgenotypes are found, the efficacy of the current vaccines should be evaluated for these new strains.

Until the early 1990s there were just three recognized species in the pestivirus genus, bovine viral diarrhea virus (BVDV), border disease virus (BDV) and classical swine fever virus (CSFV). Subsequently BVDV were divided into two different species, BVDV1 and BVDV2 and four additional putative pestivirus species have been identified, based on phylogenetic analysis. The four putative pestivirus specices, listed in chronological order of published reports, are Giraffe (isolated from one of several giraffes in the Nanyuki District of Kenya suffering from mucosal disease-like symptoms), HoBi (first isolated from fetal bovine serum originating in Brazil and later from samples originating in Southeast Asia), Pronghorn (isolated from an emaciated blind pronghorn antelope in the USA), and Bungowannah (isolated following an outbreak in pigs, resulting in still birth and neonatal death, in Australia). In addition to the emergence of putative new species of pestivirus, changes in host and virulence of recognized or ‘classic’ pestiviruses have led to reevaluation of disease control programs and management of domestic and wildlife populations.

Bungowannah virus was discovered following an outbreak of stillbirths and sudden death in young pigs. Affected animals consistently showed a myocardopathy with signs of cardiac failure. After virus isolation and PCR investigations were unsuccessful, direct fetal inoculation was undertaken. Nucleic acid purified from serum from infected fetuses was subjected to sequence-independent single-primer amplification and nucleic acid sequencing. Sequences consistent with a pestivirus were obtained. The entire genome was identified but was genetically remote from the recognized pestivirus species. This virus was not recognized by pan-pestivirus reactive monoclonal antibodies but was subsequently detected in cell cultures by immunoperoxidase staining using convalescent sow serum. Experimental infections of sows at different stages of gestation reproduced the myocarditis syndrome. Pre-weaning losses of 70 and 29% were observed following infection at days 35 and 90, respectively. Piglets infected at day 35 were shown to be persistently infected, while chronic infections were observed after fetal infection at day 55. Chronically infected piglets showed growth retardation and were viremic for up to 7 months. Myocarditis was associated with infection in late gestation (day 90). Non-pregnant sheep and cattle have been experimentally infected but with no evidence of disease. Infection of pregnant cattle in early gestation resulted in both maternal and fetal infection, but all infected fetuses mounted an antibody response to the virus. Analysis of the nucleic acid sequence confirmed that Bungowannah has a number of changes not observed in other pestiviruses. Genes encoding some of the structural proteins remain fully functional when inserted into a bovine viral diarrhea virus (BVDV) backbone. Cell culture-based studies have shown that Bungowannah virus will grow in cells extending from humans to bats as well as farm animals.

HoBi-like viruses, also referred to as bovine viral diarrhea virus 3 (BVDV-3) and atypical pestivirus, have been proposed as a new putative bovine pestivirus species. These viruses were first identified in the last decade and are currently distributed in at least three continents. Published findings suggest that these viruses may be endemic at least in parts of South America and Asia. The clinical presentations in cattle, described in field outbreaks and controlled studies, are similar to those associated with BVDV and range from subclinical to mild clinical signs, sporadically associated with reproductive losses, respiratory illness and hemorrhagic syndrome. The complete host range of HoBi-like virus is unknown, but data suggest higher adaptation of HoBi-like viruses to ruminants than swine. Acute infections, characterized by mild clinical signs, such as low-grade pyrexia and leukopenia, have been observed in both cattle and sheep. Virus has been isolated from nasal swabs indicating that virus was being shed. While seroconversion has been observed in pigs, no clinical presentation or viral shedding was evident following inoculation. While some commercial BVDV diagnostic tests may detect HoBi-like viruses, these tests do not differentiate between BVDV and HoBi-like viruses. The differentiation of BVDV and HoBi-like viruses is critical to the design of surveillance programs for these viruses.

In 2001, border disease virus (BDV) was identified as the cause of a previously unreported disease in Pyrenean chamois (Rupicapra pyrenaica) in Spain. Since then, the disease has caused a dramatic decrease, and in some cases collapse, of chamois populations and has expanded to nearly the entire distribution area in the Pyrenees. Chamois BDV was characterized as BDV-4 genotype and experimental studies confirmed that it was the primary agent of the disease. The infection has become endemic in the Central and Eastern Pyrenees. However, while most Pyrenean chamois populations have been severely affected by the disease, others have not, despite the circulation of BDV in apparently healthy individuals, suggesting the existence of different viral strategies for persisting in the host population. Changes in the interplay of pathogen, host and environmental factors may lead to the formation of different disease patterns. A key factor influencing disease emergence may be pathogen invasiveness through viral mutation. Host factors, such as behavior, immunity at the population level and genetic variability, may also have driven different epidemiological scenarios. Climatic and other ecological factors may have favored secondary infections, such as pneumonia, that under particular circumstances have been major contributing factors in the high mortality observed in some areas.

Programs for control and eradication of bovine viral diarrhea virus (BVDV) are often considered prudent when the expense of a control program within a specified time frame effectively prevents loss due to disease and the expense of control does not exceed the costs associated with infection. In some geographic areas, concerns about animal welfare or desires to reduce antibiotic usage may motivate BVDV control even when control programs are associated with a lack of financial return on investment. In other geographic areas, concerns about financial return on investment may be the key motivating factor in considering implementation of BVDV control programs. Past experiences indicate that systematic, well-coordinated control programs have a clear potential for success, while voluntary control programs in cultures of distributed decision-making often result in notable initial progress that ultimately ends in dissolution of efforts. Segmentation of the cattle industry into cow–calf producers, stocker/backgrounders, and feedlot operators amplifies the distribution of decision-making regarding control programs and may result in control measures for one industry segment that are associated with significant costs and limited rewards. Though the host range of BVDV extends well beyond cattle, multiple eradication programs that focus only on testing and removal of persistently infected (PI) cattle have proven to be effective in various countries. While some individuals consider education of producers to be sufficient to stimulate eradication of BVDV, research surrounding the adoption of innovative health care procedures suggests that the process of adopting BVDV control programs has a social element. Collegial interactions and discussions may be crucial in facilitating the systematic implementation necessary to optimize the long-term success of control programs. Compulsory control programs may be considered efficient and effective in some regions; however, in a nation where individual identification of cattle remains voluntary, the likelihood of effective compulsion to control BVDV within a farm or ranch appears to be very unlikely. While currently available diagnostic tests are sufficient to support BVDV eradication via systematic, well-coordinated programs, the development of a diagnostic procedure to safely and consistently detect the gestation of a PI fetus after 5 months of gestation would be a valuable research breakthrough. This desired testing modality would allow diagnosis of PI calves, while the dam continues to provide biocontainment of the infected fetus. This development could speed the progress of control programs in achieving the goal of BVDV control and eventual eradication.

Classical swine fever (CSF) is endemic in large parts of the world and it is a major threat to the pig industry in general. Vaccination and stamping out have been the most successful tools for the control and elimination of the disease. The systematic use of modified live vaccines (MLV), which are very efficacious and safe, has often preceded the elimination of CSF from regions or countries. Oral vaccination using MLV is a powerful tool for the elimination of CSF from wild boar populations. Bovine virus diarrhea (BVD) is endemic in bovine populations worldwide and programs for its control are only slowly gaining ground. With two genotypes BVD virus (BVDV) is genetically more diverse than CSF virus (CSFV). BVDV crosses the placenta of pregnant cattle resulting in the birth of persistently infected (PI) calves. PI animals shed enormous amounts of virus for the rest of their lives and they are the reservoir for the spread of BVDV in cattle populations. They are the main reason for the failure of conventional control strategies based on vaccination only. In Europe two different approaches for the successful control of BVD are being used: Elimination of PI animals without or with the optional use of vaccines, respectively.