Материал: Bovine Viral Diarrhea Virus Diagnosis, Management, and Control

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PROGRESS IN BVDV RESEARCH

Since the first publication on bovine viral diarrhea virus (BVDV) 60 years ago (Olafson et al., 1946), significant progress has been made in elucidating the pathogenesis, transmission, diagnosis, and molecular virology of this virus. We have come to understand that the pathogenesis of BVDV is complicated and that it produces a multifaceted disease (Bolin et al., 1985; Brownlie et al., 1984; Corapi et al., 1989). Monoclonal antibodies (Mabs) have been developed (Moennig et al., 1987) and the genome of BVDV has been completely sequenced (Collett et al., 1988). Antigenic and genomic diversity has been found to be a hallmark of BVDV, making the control of this virus difficult. In addition to different biotypes (Gillespie et al., 1960), different genotypes and subgenotypes have now been identified (Pellerin et al., 1994; Ridpath et al., 1994). Biotype differences in cytopathology in culture are associated with the production of a nonstructural protein (NS3 or P80) in the cytopathic strains (Meyers et al., 1991). Cytopathic effect observed in vitro (i.e., cytopathic biotype) does not correlate with virulence in vivo, because all highly virulent viruses belong to the noncytopathic biotype (Ridpath et al., 2000). Although hemorrhagic syndrome has been associated only with viruses from the BVDV 2 genotype, variation in virulence exists in both the BVDV 1 and BVDV 2 genotype (Evermann and Ridpath, 2002; Fulton et al., 2000; Fulton et al., 2002; LieblerTenorio et al., 2003).

Numerous studies have been undertaken to elucidate the mechanism of development of persistently infected (PI) animals and how to control them (Harding et al., 2002; Ohmann, 1982; Ohmann et al., 1982; Van Campen and Woodard, 1997). It is widely accepted that PI animals are a major source of virus on the farm and in feedlots. Although viral

shed is limited and normally confined to a period of less than 7 days, transiently infected animals can also be a source of virus to herdmates. Both acutely and persistently infected bulls can shed virus in their semen with a minimal effect on the traditional measures of semen quality (Givens et al., 2003; Kirkland et al., 1991; Kommisrud et al., 1996; Revell et al., 1988). The presence of BVDV in semen leads to virus transmission by the reproductive route, resulting in abortions, early embryonic death, congenital infections and PI animals (Givens et al., 2003; Kirkland et al., 1991; Kommisrud et al., 1996; Kirkland et al., 1997; Meyling and Jensen, 1988; Paton et al., 1990; Schlafer et al., 1990).

Major advances have been made in detecting BVDV infection, including the use of monoclonal antibody– and polymerase chain reaction–based tests. Although BVDV may be spread by animals that are either persistently or acutely infected, the main emphasis until now has been on the detection of PI animals. This is because the removal of PI animals is considered to be integral to an effective control strategy. Eradication programs in Sweden, Finland, and Denmark rely on nonvaccination of cattle so that positive animals can be identified and removed easily (Greiser-Wilke et al., 2003). These programs are reported to be successful in reducing BVDV-positive herds. In Germany, vaccination with killed vaccine followed by a booster dose of modified live vaccine (MLV), in addition to testing and removing PI animals, is used to reduce virus circulation in the herd (Moennig and Greiser-Wilke, 2003). In the U.S., reliance is placed on detection and removal of PI animals and vaccination of breeding animals before conception. Recent research suggests that, to be effective, BVDV vaccines should contain at least a BVDV 1 and a BVDV 2 strain (Fulton et al., 2003).

BVDV research as summarized above has benefited from the efforts of a cadre of outstanding scientists and diagnosticians, as reported and illustrated by the authors of the preceding chapters. However, BVDV has proven to be a difficult and challenging subject and despite these efforts much remains to be done. As this book goes to press there is gathering momentum for the development and implementation of a national program for BVDV control in the United States. Although eradication of BVDV in the U.S. may be a difficult goal to achieve, the reduction of the losses currently caused by BVDV is a readily attainable goal and is well worth pursuing. Ideally, the drive to reduce BVDV losses would be multifaceted and widely implemented. It would require the cooperation of producers, practitioners, diagnosticians, and regulators, and a refocusing of research and control efforts.

REFOCUSING BASIC RESEARCH

NONCYTOPATHIC BVDV

To date, heavy emphasis has been placed on examining differences between cytopathic and noncytopathic viruses in vitro. While intriguing from a scientific standpoint, such research does little towards reducing the incidence of BVDV in the field. Cytopathic viruses are rare and isolated only in association with mucosal disease or postvaccinal disease resulting from inoculation with a cytopathic BVDV vaccine. Mucosal disease, although an interesting phenomenon, is not a source of major economic loss for producers. The major economic impact of BVDV infection is the result of losses associated with reproductive or respiratory disease, which are almost always the result of infection with a noncytopathic virus. In contrast, no clinical outbreaks of acute disease have been traced to infection with a cytopathic BVDV.

Immunosuppression and acerbation of secondary infections, associated with infection with noncytopathic BVDV, also contribute to economic losses. There is no evidence to indicate that acute, uncomplicated infections with cytopathic BVDV are more clinically severe than infection with noncytopathic BVDV. In fact, the most clinically severe forms of acute BVDV infections are associated with noncytopathic BVDV. Thus, comparing cytopathic and noncytopathic viruses in vitro yields little information that would help limit BVDV infections in vivo. Efforts to limit the damage caused by BVDV infections would be better served by research that addresses the real significance of noncytopathic

BVDV strains and the host’s response to them. In addition, the nature of immunosuppression and of protective immune response engendered by BVDV should be studied. Because noncytopathic virus may establish persistent infections, all available BVDV vaccines contain only cytopathic BVDV. It is not known, however, if cytopathic BVDV contained in vaccines are any safer than the noncytopathic viruses, especially for fetuses.

T-CELL RESPONSES

Considerable amount of information is available on B-cell immune response to BVDV vaccines, but little information is available regarding the T-cell responses. This is partly due to the availability of simple and reliable technology to examine and compare B-cell responses, as expressed by neutralizing antibodies present in serum. Unfortunately, such technology is not yet available for comparing T-cell responses, although it appears that the T-cell response is as important, if not more important, as B-cell response in the development of acquired immunity against BVDV. Research that focuses on methods to improve T-cell response to vaccination is sorely needed. This is dependent upon developing simple, robust, and reliable methods for measuring and comparing T-cell responses in infected, vaccinated, and nonvaccinated animals.

ACUTE, PROLONGED INFECTIONS

Historically, BVDV infections have been categorized as acute or persistent. Persistent infections are defined as lifelong infections resulting from in utero exposure of the animal to a noncytopathic BVDV. Lifelong infections result because the animal develops a specific immune tolerance for the virus to which it was exposed in utero. Acute infections, on the other hand, are defined as infections in which the immune system clears the virus within 14 days. However, the real picture is somewhat more complicated. For example, some animals exposed after birth (acute infection) may mount an immune response but fail to clear the virus within 14 days, some animals may clear the virus after a prolonged viral shed, and others may allow the virus to replicate in immunologically privileged sites such as testes and ovaries (see Chapter 9).

The damage resulting from acute infections may not be over after the virus has been cleared. Thus, there may be lingering problems that are not detected until several months after viremia has passed. Prolonged infections and persistent infections within privileged sites also contribute to the spread