Viruses and viral diseases have been at the centers of science, agriculture, and medicine for millennia, and some of our greatest challenges and triumphs have involved virology. Smallpox is a prime example: humankind's greatest killer, which literally changed the course of history during the European conquest of the New World, is also the only disease ever eradicated from the globe. This remarkable achievement began with Edward Jenner's scientific demonstration in 1796 that inoculation with cowpox lesions provided protection against the far-more-virulent variola major virus. A concerted worldwide vaccination effort against smallpox led by the World Health Organization resulted in the eradication of the disease by 1979. The smallpox vaccination breakthrough was only the first in a series of important investigations and discoveries inspired by the study of viruses. Tables and list many of these advances and highlight the contributions of virology and virologists to our understanding of basic cellular functions and disease mechanisms.
Landmarks in the study of virusesa
Much of the initial attention of virologists was focused on viruses as disease-causing agents, and great progress continues to be made in this area. Many acute viral infections are prevented or controlled in much of the world through vaccination and other public health measures. As a result, viral scourges such as measles, poliomyelitis, rabies, and yellow fever are now rare in the developed world. Numerous effective antiviral drugs are also in widespread use. We now recognize that a substantial fraction of the world cancer burden is caused by viral infections, most commonly hepatitis B virus and human papillomavirus infections, and both can be prevented by vaccination. All of these advances flowed from basic studies of viral replication, transmission, and pathogenesis. However, substantial challenges remain. New viruses periodically emerge and cause great personal and societal tragedy. AIDS, caused by human immunodeficiency virus type 1 (HIV-1), remains the defining epidemic of our time, the true cost of which cannot be calculated. 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. The emergence of a new influenza pandemic or a viral bioterrorism attack could have catastrophic consequences on public health, commerce, and civic discourse.
Viruses also cause serious diseases in plants and livestock. The 2001 epidemic of foot-and-mouth disease in the United Kingdom devastated its beef industry. Plum pox virus, 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.
Beyond their medical and agricultural importance, viruses are great teachers, and their lessons are not restricted to viral diseases. Viral replication is strictly dependent on cell structure, metabolism, and biochemical machinery. As a consequence, viral gene products interact with crucial regulatory nodes that control cell function, a situation that facilitates the identification and characterization of these nodes and the networks they control. Indeed, the roster of important discoveries uncovered by studies of viral replication and transformation is long: the existence of 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, to name just a few. The structural biology revolution, the initially outlandish idea that life processes can be understood at the chemical and eventually at the atomic level, was championed by the crystallization of tobacco mosaic virus by Wendell Stanley in the 1930s. This line of inquiry has produced high-resolution images of the 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 the discovery of viroids and prions and the concept of protein-folding diseases.
Viral genomes encode gene products that modulate host defenses, including the immune response, an elaborate system that evolved in large part to protect us against invading microorganisms like viruses. Ideally, pathogens are cleared by immune defenses with minimum damage to the host. However, in the process, the immune defenses themselves can also cause damage (immunopathology). Indeed, much of viral clinical disease is immunopathological in nature, as shown in infections ranging from the common cold to AIDS. Studies of the interactions between viruses and cells have revealed many aspects of immunity, including the elucidation of histocompatibility antigen function, intrinsic cell defense mechanisms such as apoptosis, interferons, and RNA interference, and sophisticated viral countermeasures to evade or antagonize host immune responses. In fact, this discipline has been coined “anti-immunology” by some to highlight the close evolutionary relationship between the vertebrate immune system and microbial pathogens.
Many technologies employed to study cellular genes were first developed and perfected by using smaller and more easily manipulated viral genomes, including restriction enzyme mapping, molecular cloning, and genome sequencing. Indeed, the field of genetic engineering and the biotechnology industry were incubated in virology laboratories. Viruses and viral gene products have also emerged as valuable tools to study many aspects of biology and, potentially, to treat disease. These tools include reverse transcriptase for the synthesis of cDNA, viral vectors for gene delivery and protein production, transgenic animal technology, vaccination, and oncolytic therapy, which attempts to harness the capacity of some viruses to specifically infect and kill cancer cells. Studies to determine whether this approach has efficacy in the treatment of human cancers are under way.
Critical knowledge may also come from unexpected sources. Simple, highly expressed plant viruses have been developed into model systems to identify host factors involved in viral replication, translation, and other processes fundamental to all viruses. Plant viruses are also excellent tools for biotechnology and nanotechnology. For the latter, virions provide natural reaction chambers for the precise synthesis of nanoparticles, as well as digital memory components when complexed with metals.
As briefly outlined in this section, virology played a major role in 20th-century biology. The numerous Nobel prizes awarded to virologists are one measure of the impact of virology (Table ). In this essay, we highlight some of the areas where virology will continue to address substantial challenges and provide new and important insights.