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Virology in the 21st Century


Viruses remain at the center of science, agriculture, and medicine, providing some of our greatest challenges and triumphs

L. W. Enquist for the Editors of
The Journal of Virology

L. W. Enquist is Henry L. Hillman Professor and Chair of the Department of Molecular Biology and Professor in the Princeton Neuroscience Institute at Princeton University, Princeton, N.J.

Editor's Note
This article was adapted from a longer minireview prepared for and published in the Journal of Virology (83:5296-5308).


  • Virology continues to flourish as a discipline at the center of science, agriculture, and medicine, providing great lessons in basic and applied biology.
  • Viruses will be increasingly viewed as part of a complex microbial ecosystem where a single host is infected with a plethora of microbes, including many viruses.
  • We can count on uncovering new or previously unrecognized viral infections in plants, animals, and humans, for whom such infections often prove zoonotic.
  • One sea change in virology is that we now function in a cross-disciplinary environment, which is key to training the next generations of virologists.

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Viruses and viral diseases have been at the center of science, agriculture, and medicine for millennia, and some of our greatest challenges and triumphs have involved virology. Smallpox is a prime example. This greatest killer of humankind changed the course of history during the European conquest of the New World and is also the only disease ever eradicated. This remarkable achievement began with Edward Jenner in 1796 and concluded by 1979 with a worldwide vaccination effort led by the World Health Organization. The smallpox vaccination breakthrough was only the first in a series of important investigations inspired by the study of viruses, while the numerous Nobel Prizes awarded to virologists are another measure of the impact of this discipline (see table).  table.pdf

Viruses as Disease Agents

Many viral infections are prevented or controlled through vaccination and other public health measures, making one-time scourges such as measles, poliomyelitis, rabies, and yellow fever now rare in the developed world. Numerous effective antiviral drugs are also in widespread use. We now recognize that some cancers are caused by viral infections, including hepatitis B virus and human papillomavirus, that also can be prevented by vaccination. However, substantial challenges remain.

New viruses periodically emerge and cause great personal and societal tragedy. Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus-1 (HIV-1), remains the defining epidemic of our time. Although the severe acute respiratory syndrome (SARS) epidemic was brief, dengue and West Nile viruses continue to smolder, and Chikungunya virus, monkeypox virus, and Ebola and other hemorrhagic fever viruses crouch in the darkness. H5N1 avian influenza virus continues to sporadically infect humans in Southeast Asia and elsewhere, and this year an H1N1 flu strain emerged and spread rapidly across the globe. The emergence of a deadlier influenza pandemic or a viral bioterrorism attack could have catastrophic consequences on public health, commerce, and civic discourse.

Viruses also cause serious disease in plants and livestock. The 2001 epidemic of foot-and-mouth disease in the United Kingdom devastated its beef industry. Plum poxvirus, which has decimated stone fruit trees in Europe since the early 1900s, has now spread to the United States and Canada. Viruses have been implicated in a disease that is ravaging our honeybees, threatening natural pollination cycles and thus much of agriculture. During the 1990s, efforts to apply RNA interference to protect crops against infections by highly destructive viruses were halted because of unsubstantiated fears about this kind of genetic modification. With the prospect of worldwide food shortages caused by climate change, decreased investment in genetic technology has serious implications for human health. These and similar concerns provide a rich opportunity for the scientific community to advance ideas in the public domain about new developments and evidence-based risk assessments.

Important Role of Viruses in Basic Biology

Beyond medicine and agriculture, the study of viruses provides great lessons in basic biology. Viral replication is strictly dependent on cell structure, metabolism, and biochemical machinery, and, thus, the roster of important discoveries uncovered by studies of viral replication and transformation is long: the existence of messengerRNA (mRNA) and mRNA processing, including splicing, capping, and polyadenylation; transcriptional control elements and transcription factors; gene silencing mechanisms; cellular oncogenes and tumor suppressor proteins; and signal transduction pathways and tyrosine kinases.

The structural biology revolution was championed by crystallization of tobacco mosaic virus by Wendell Stanley in the 1930s. This line of inquiry produced high-resolution structures of viral proteins and virus particles themselves, the largest biological structures known at the atomic level. Molecular biology emerged from studies of bacterial viruses. Studies of unconventional viruses resulted in discovery of viroids and prions and the concept of protein-folding diseases.

Viral genomes encode products that modulate host defenses, including the immune response that, ideally, clears pathogens with minimum damage to the host. However, much of viral clinical disease is immunopathological in nature, as shown in infections ranging from the common cold to AIDS. Studies of interactions between viruses and cells continue to reveal complex host responses and countermeasures, including histocompatibility antigen functions, intrinsic cell defense mechanisms such as apoptosis, interferons, and RNA interference, and viral countermeasures to evade or antagonize host responses-a discipline called "anti-immunology."

Virology Intertwined with Technology Development

In the 21st century, we can begin to identify new families of organisms and viruses by high-speed sequencing of RNA and DNA. For example, deep sequencing of mixed populations can reveal novel virus families. Indeed, new polyomaviruses, marine viruses, and bacteriophages have been identified using sequence-based techniques coupled with genomic and metagenomic analyses. Strikingly, some of these viral proteins show little genetic similarity to those from better- known viruses.

In a similar vein, high-throughput sequencing and gene-mapping techniques, the availability of the genome sequence from humans and other organisms, and proteomics and metabolomics will provide us with the ability to study host determinants of viral virulence in ways previously unimagined. Exciting discoveries notwithstanding, identifying new viruses brings a serious challenge. Are these viruses true pathogens or do they have symbiotic relationships with their hosts? For example, perhaps these agents stimulate local and systemic immune responses that protect against or suppress responses that contribute to pathogenesis by more virulent microbes.

Instead of studying one gene or gene product at a time, examining large groups of them using a systems biology approach allows the identification of fundamental biological networks. An important premise of systems biology is that information flows through networks, and disease arises when these networks are perturbed, causing changes in network architecture and dynamics. Technological advances will allow in vitro study of viral infections using conditions that more precisely mimic in vivo environments.

Viruses will be increasingly viewed not in isolation with their hosts, but in the real world of a microbial ecosystem where a single host is infected with a plethora of microbes, including many viruses. For example, some viral infections are associated with atherosclerosis and obesity. However, whether the associated viral infections are causal, serve as essential cofactors, or are irrelevant is not known. Components of the initial host inflammatory response to an infection, namely cytokines, chemokines, and cells of the innate and adaptive immune systems, can regulate the outcome of infection by a second agent. The degree of susceptibility and response of a virus-infected cell to a secondary infection can be modulated by many cellular factors.

One of the tenets of systems biology is that networks process information and the output can vary depending on the action at key nodes of the network. Therefore, an important use of systems biology is to perturb networks and analyze outcomes. Viral infections provide the opportunity to take a system from state A (uninfected) to state B (infected) with synchrony and technical control. This approach to generate and test hypotheses will be a powerful tool to understand homeostatic control and viral pathogenesis.

Emerging Infections, Natural and Synthetic

We continue to uncover new or previously unrecognized viral infections in plants, animals, and humans, for whom such infections often prove zoonotic, meaning the pathogen moves from wild or domesticated animals to humans. Improved surveillance, more rapid reagent sharing and information transfer, more effective quarantine procedures, and various public health measures will undoubtedly contribute to controlling emerging diseases, but increasing attention and resources are likely to be devoted to expanding the roster of antivirals and vaccines.

One view is that we should accelerate development of new antiviral strategies to protect the public from these emerging infections. To be effective, antiviral drugs must be safe, potent, and administered soon after infection. These requirements constitute substantial impediments to drug discovery, which has limited the number of antivirals in clinical use for acute infections relative to antibiotics. Nonetheless, numerous highly effective antiviral drugs are in widespread use, particularly against HIV. Although we must certainly prepare for future threats, antiviral drug development should not ignore viruses that currently account for a substantial burden of disease.

Meanwhile, vaccines remain among the most cost-effective means of preventing infectious disease morbidity and mortality. However, there are several challenges to developing vaccines. First, we must understand the basic biology of viral evolution and quasispecies. Second, we need to define what constitutes a protective immune response. Third, we have to acknowledge the economics of vaccine development and the risk to the private sector, recognizing that the necessity of immunizing a healthy naive population to prevent a disease will be unacceptable if there are significant vaccine-associated adverse events. Even greater challenges arise in introducing vaccines to the public. Many believe that children already are "overvaccinated" in infancy. In addition, there is a public perception that vaccines cause diseases such as autism or attention deficit disorder despite substantial evidence to the contrary. Successful vaccine efforts will require both sound science and forceful public advocacy.

Highly pathogenic viruses, either in their wild-type state or after genetic manipulation, could be used for terrorism. Although risks of virus-based bioterrorism are considered low, virologists and the scientific community should be vigilant and guard against such misuses of scientific information.

Nature remains dangerous enough, acting through zoonoses such as AIDS, which moved from primates to humans, and the SARS-coronavirus, which was transmitted to humans from bats and civet cats. Heightened concerns about potential viral pandemics and bioterrorism have resulted in the construction of high-containment research facilities and increased scrutiny of the safety of research on viral pathogens, particularly those designated "select agents" by officials  of the Centers for Disease Control and Prevention or the U.S. Department of Agriculture. This designation mandates strict regulatory oversight, which should be balanced by consideration of the risks of hindering research. Because many select agents are endemic in some areas of the world, regulatory decisions about "select agents" should be based on realistic risk assessments.

Training Virologists while Expanding their Portfolios

What constitutes optimum training for virologists? Training the next generation will require more diverse course offerings, enhanced opportunities, especially involving interdisciplinary collaboration and computational approaches, and instruction in teamwork. Systems biology approaches, large-scale genetic screens, metagenomics of host and viral genes from related viruses, and imaging technologies produce enormous amounts of information that can be difficult to integrate into conceptual frameworks. Methods to search, screen, recover, and use this information will require virologists with special expertise in computational methods and information technology.

Continuing research should not only focus on conventional viruses but also enhance our understanding of new classes of subviral infectious agents such as prions. Prions are infectious, misfolded host-derived proteins that can spread disease or phenotypic traits without carrying their own nucleic acid genome. Practical diagnostic tests and treatments must be developed for mammalian prion diseases such as bovine spongiform encephalopathy and Creutzfeldt-Jacob disease. A number of common protein misfolding diseases such as Alzheimer's disease and other amyloidoses might be transmissible due to prion-like behavior of misfolded proteins. Such possibilities are another important area for investigation.

The general trends likely to drive virology research in the next decade include systems biology of virus-host interactions, viral ecology and the virosphere, evolution of viruses, and improved vaccines and therapeutics. Regardless of the path virology takes in the coming years, history has proved repeatedly that understanding viruses leads to valuable insights into basic biological phenomena.

We anticipate a rich future for viral pathogenesis research. If we could point to one sea change in virology that will affect us all, it would be that we now function in a cross-disciplinary environment. Those in other disciplines who do not master the biology of viruses are likely to provide technical expertise, but they will find it more difficult to share with virologists the joy of understanding fundamental biology, making discoveries, and improving the health and well-being of our planet.

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