Bovine viral diarrhea virus (BVDV) is an important infectious disease agent that causes significant reproductive and economic losses in the cattle industry worldwide. Although BVDV infection is known to cause poor fertility in cattle, a greater part of the underlying mechanisms particularly associated with early reproductive losses are not clearly understood. Previous studies reported viral compromise of reproductive function in infected bulls. In females, BVDV infection is thought to be capable of killing the oocyte, embryo or fetus directly, or to induce lesions that result in fetal abortion or malformation. BVDV infections may also induce immune dysfunction, and predispose cattle to other diseases that cause poor health and fertility. Other reports also suggested BVDV-induced disruption of the reproductive endocrine system, and a disruption of leukocyte and cytokine functions in the reproductive organs. More recent studies have provided evidence of viral-induced suppression of endometrial innate immunity that may predispose to uterine disease. Furthermore, there is new evidence that BVDV may potentially disrupt the maternal recognition of pregnancy or the immune protection of the conceptus. This review brings together the previous reports with the more recent findings, and attempts to explain some of the mechanisms linking this important virus to infertility in cattle.

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.

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.

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.

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.

Viral disease is one of the major causes of financial loss and animal suffering in today's cattle industry. Increases in global commerce and average herd size, urbanization, vertical integration within the industry and alterations in global climate patterns have allowed the spread of pathogenic viruses, or the introduction of new viral species, into regions previously free of such pathogens, creating the potential for widespread morbidity and mortality in naïve cattle populations. Despite this, no antiviral products are currently commercially licensed for use in bovine medicine, although significant progress has been made in the development of antivirals for use against bovine viral diarrhea virus (BVDV), foot and mouth disease virus (FMDV) and bovine herpesvirus (BHV). BVDV is extensively studied as a model virus for human antiviral studies. Consequently, many compounds with efficacy have been identified and a few have been successfully used to prevent infection in vivo although commercial development is still lacking. FMDV is also the subject of extensive antiviral testing due to the importance of outbreak containment for maintenance of export markets. Thirdly, BHV presents an attractive target for antiviral development due to its worldwide presence. Antiviral studies for other bovine viral pathogens are largely limited to preliminary studies. This review summarizes the current state of knowledge of antiviral compounds against several key bovine pathogens and the potential for commercial antiviral applications in the prevention and control of several selected bovine diseases.

Infections with Bovine viral diarrhea virus (BVDV) are not limited to cattle, but may be detected in various species in the mammalian order Artiodactyla. Despite epidemiological evidence of BVDV infections in species other than cattle, current knowledge regarding the impact of BVDV on heterologous species is incomplete. In heterologous hosts, BVDV infections with clinical signs analogous to those in cattle have been described and include disease of multiple organ systems, most notably the reproductive tract and immune system. Clinical infections may negatively impact the health and well-being of heterologous species, including camelids and captive and free-ranging wildlife. Of additional importance are BVDV infections in small ruminants and swine where difficulties arise in laboratory testing for Border disease virus (BDV) and Classical swine fever virus (CSFV), respectively. Pestiviruses are antigenically closely related and their cross-reactivity requires additional efforts in virological testing. In cattle populations, persistently infected animals are considered the main source of BVDV transmission. This phenomenon has also been detected in heterologous species, which could facilitate reservoirs for BVDV that may be of great importance where control programs are in progress. This review summarizes the current epidemiological and clinical knowledge on heterologous BVDV infections and discusses their implications.

The aim of the present study was to evaluate the development and ultrastructure of preimplantation bovine embryos that were exposed to bovine viral diarrhea virus (BVDV) in vitro.

The embryos were recovered from superovulated and fertilized Holstein-Friesian donor cows on day 6 of the estrous cycle. Compact morulae were microinjected with 20 pl of BVDV suspension (105.16 TCID50/ml viral stock diluted 1:4) under the zona pellucida (ZP), then washed in SOF medium and cultured for 24–48 h. Embryos were evaluated for developmental stages and then processed immunocytochemically for the presence of viral particles, using fluorescent anti-BVDV–FITC conjugate. Ultrastructure of cellular organelles was analysed by transmission electron microscopy (TEM).

After microinjection of BVDV under the ZP, significantly more (p < 0.001) embryos (83.33%) were arrested at the morula stage compared with the intact control (30.33%). Immunocytochemical analysis localized the BVDV–FITC signal inside the microinjected embryos. TEM revealed: (i) the presence of virus-like particles in the dilated endoplasmic reticulum and in cytoplasmic vacuoles of the trophoblast and embryoblast cells; (ii) the loss of microarchitecture: and (iii) abnormal disintegrated nuclei, which lacked reticular structure and the heterochromatin area. In all, the embryo nuclear structure was altered and the microarchitecture of the nucleolus had disappeared when compared with the nuclei from control embryos. Dilatation of the intercellular space and the loss of the intercellular gap junctions were often observed in bovine BVDV-exposed embryos.

These findings provide evidence for the adverse effect of BVDV virus on the development of bovine embryos, which is related to irreversible changes in the ultrastructure of cell organelles.