Animal models in virus research: their utility and limitations.

Viral diseases are important threats to public health worldwide. With the number of emerging viral diseases increasing the last decades, there is a growing need for appropriate animal models for virus studies. The relevance of animal models can be limited in terms of mimicking human pathophysiology. In this review, we discuss the utility of animal models for studies of influenza A viruses, HIV and SARS-CoV in light of viral emergence, assessment of infection and transmission risks, and regulatory decision making. We address their relevance and limitations. The susceptibility, immune responses, pathogenesis, and pharmacokinetics may differ between the various animal models. These complexities may thwart translating results from animal experiments to the humans. Within these constraints, animal models are very informative for studying virus immunopathology and transmission modes and for translation of virus research into clinical benefit. Insight in the limitations of the various models may facilitate further improvements of the models.

Biosafety of non-human therapeutic viruses in clinical gene therapy.

The concept of using viruses as oncolytic agents is not a new one. In an effort to improve the applicability of viral anti-cancer agents various non-human viruses are being evaluated preclinically and clinically. The application of replication- competent non-human viruses poses new potential hazards, i.e. those associated with the possible adaptation of the therapeutic viruses to the human hosts. Therefore it is essential to weigh the potential benefits for the patients against the risk for the patients, their close contacts, and the greater public. Many aspects of such assessment parallel with the risks and dilemmas associated with the use of live porcine cells, tissues and organs in a clinical xenotransplantation setting. In this review we will summarize the potential biological hazards and list the points that need to be considered in a formal biosafety risk evaluation. The risk evaluation should include the possible environmental aspects of the non-human viruses used, also in case the non-human viruses are not formally designated as genetically modified organisms.

Emergence of viral diseases: mathematical modeling as a tool for infection control, policy and decision making.

Mathematical modeling can be used for the development and implementation of infection control policy to combat outbreaks and epidemics of communicable viral diseases. Here an outline is provided of basic concepts and approaches used in mathematical modeling and parameterization of disease transmission. The use of mathematical models is illustrated, using the 2001 UK foot-and-mouth disease (FMD) epidemic, the 2003 global severe acute respiratory syndrome (SARS) epidemic, and human influenza pandemics, as examples. This provides insights in the strengths, limitations, and weaknesses of the various models, and demonstrates their potential for supporting policy and decision making.

Reappraisal of biosafety risks posed by PERVs in xenotransplantation.

Donor materials of porcine origin could potentially provide an alternative source of cells, tissues or whole organs for transplantation to humans, but is hampered by the health risk posed by infection with porcine viruses. Although pigs can be bred in such a way that all known exogenous microorganisms are eliminated, this is not feasible for all endogenous pathogens, such as the porcine endogenous retroviruses (PERVs) which are present in the germline of pigs as proviruses. Upon transplantation, PERV proviruses would be transferred to the human recipient along with the xenograft. If xenotransplantation stimulates or facilitates replication of PERVs in the new hosts, a risk exists for adaptation of the virus to humans and subsequent spread of these viruses. In a worst-case scenario, this might result in the emergence of a new viral disease. Although the concerns for disease potential of PERVs are easing, only limited pre-clinical and clinical data are available. Small-scale, well-designed and carefully controlled clinical trials would provide more evidence on the safety of this approach and allow a better appreciation of the risks involved. It is therefore important to have a framework of protective measures and monitoring protocols in place to facilitate such initially small scale clinical trials. This framework will raise ethical and social considerations regarding acceptability.

Cross-species transfer of viruses: implications for the use of viral vectors in biomedical research, gene therapy and as live-virus vaccines.

All living organisms are continuously exposed to a plethora of viruses. In general, viruses tend to be restricted to the natural host species which they infect. From time to time viruses cross the host-range barrier expanding their host range. However, in very rare cases cross-species transfer is followed by the establishment and persistence of a virus in the new host species, which may result in disease. Recent examples of viruses that have crossed the species barrier from animal reservoirs to humans are hantavirus, haemorrhagic fever viruses, arboviruses, Nipah and Hendra viruses, avian influenza virus (AI), monkeypox virus, and the SARS-associated coronavirus (SARS-CoV). The opportunities for cross-species transfer of mammalian viruses have increased in recent years due to increased contact between humans and animal reservoirs. However, it is difficult to predict when such events will take place since the viral adaptation that is needed to accomplish this is multifactorial and stochastic. Against this background the intensified use of viruses and their genetically modified variants as viral gene transfer vectors for biomedical research, experimental gene therapy and for live-vector vaccines is a cause for concern. This review addresses a number of potential risk factors and their implications for activities with viral vectors from the perspective of cross-species transfer of viruses in nature, with emphasis on the occurrence of host-range mutants resulting from either cell culture or tropism engineering. The issues are raised with the intention to assist in risk assessments for activities with vector viruses.