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Smallpox, or variola, virus has killed more human beings than any other infectious agent. Fortunately, smallpox virus has only one host-humans -- which made it possible to eradicate it. In 1967, the World Health Organization (WHO) initiated a brilliant campaign that, within 10 years, eradicated smallpox virus from human populations, the last case occurring in Somalia in 1977. Illustration: John Overmeyer Soon after, the question arose as to what to do with the smallpox isolates stored in laboratories throughout the world. In 1981, WHO recommended that all isolates be destroyed, with the exception of stocks held at the Centers for Disease Control in Atlanta and at the Institute for Viral Preparations in Moscow. WHO also recommended that the genomes of several smallpox virus isolates be cloned into plasmids and sequenced. With that achieved, some scientists and government officials claimed that the smallpox virus stocks in Atlanta and Moscow are superfluous, have no future value, and should be destroyed (K.Y. Kreeger, The Scientist, Nov. 14, 1994, page 1). After much discussion, the World Health Assembly of WHO recommended in May that all remaining stocks of smallpox virus be destroyed by June 30, 1999. While this recommendation has sparked a great deal of heated debate, one point remains clear. There are no good scientific reasons for destroying smallpox virus, but there are overwhelmingly compelling ones for keeping the stocks. Consider the argument. As humans are brought into ever closer contact by mounting population pressures and increased mobility, we are encountering more and more infections both by known viruses in new situations and by "new and emerging" viruses. Characterization in molecular terms of the processes and mechanisms involved in viral pathogenesis is therefore becoming of vital importance. Now it turns out that the genome of smallpox virus, the most "successful" of all human viruses, encodes a unique array of proteins that interact with and neutralize components of human antiviral defense mechanisms. Thus, detailed knowledge of how smallpox virus causes disease could well provide vital information in efforts to control infection by HIV, Ebola, and other emerging viruses. Since pathogenesis is the balance of many interactions that depend not only on the nature but also on the relative amounts of the various viral gene products involved, this knowledge can be obtained only by studying the infectious smallpox virus. Attempting to discover the outcome of viral infections in intact hosts through a knowledge of only the functions of viral gene products would be like attempting to determine how animals run, climb, jump, swim, or fly knowing only their isolated limbs and organs. Thus, smallpox virus has much to teach us about viral pathogenesis. The major reasoning behind the call for destruction is that, now that the entire smallpox genome has been cloned into plasmids and sequenced, all knowledge concerning the information stored in it can be derived via studies of its cloned genes. Maintaining the infectious virus would, on one hand, present an unconscionable risk, since it might conceivably fall into the hands of terrorists who could use it to unleash devastating epidemics in unvaccinated populations. On the other hand, destroying the last stocks of it would provide a fitting finale to its eradication from human populations. There are many who are not convinced by these arguments. The fear that smallpox virus will fall into the hands of terrorists is surely exaggerated; it is hard to believe that the United States and Russia lack the resources to protect several dozen vials. Nor is it certain that the virus stocks under discussion are the only sources of smallpox in existence (W.K. Joklik et al., Science,262: 1225-6, 1993). The cadavers of smallpox patients preserved in permafrost, which sometimes become exposed, could contain infectious virus. Smallpox virus specimens could still exist in laboratories in various parts of the world. Moreover, monkeypox virus, a close relative of smallpox virus, causes severe disease in humans similar to smallpox. Although monkeypox virus is transmitted poorly, it might acquire high transmissibility via mutation or recombination. Thus, it is by no means certain that the destruction of the virus stocks in Atlanta and Moscow would remove the threat of smallpox from the world. Proponents of destruction aver that such destruction would "send the clearest possible signal to all countries that any work with live smallpox virus will from now on be regarded as a criminal activity punishable by national and international authorities, and that the mere possession of such virus is illegal" (B.W. Mahy et al., Science, 262:1223-4, 1993). Regrettably, taking the high road in this manner is unlikely to deter unsanctioned behavior; setting good examples rarely prevents criminal activity. It should also be noted that DNA synthesizers will soon be capable of producing 1,000 nucleotide stretches of DNA overnight (B. Roizman et al., Infectious Agents and Disease, 3:215-7, 1994). Thus, it will soon be feasible to synthesize smallpox virus genes (all of the sequences have been published) and to insert them into the genomes of some other poxvirus. This could generate an even more dangerous and uncontrollable virus because it would be a new virus. Characterization of the molecular pathogenesis of smallpox virus-that is, characterization of the manner in which the unique library of smallpox virus proteins overcomes human antiviral defense mechanisms-provides information of crucial importance for controlling other lethal viruses. with viruses triggers a variety of responses. Among them are the formation of interferon; the dispatch of white cells to the site of infection, which causes inflammation; the generation of T cells that recognize and destroy the infected cells and of B cells that produce antibodies against proteins specified by the infecting virus; and the destruction, via apoptosis, of infected cells by specific cytotoxic T lymphocytes (CTL) that recognize the fragments of viral proteins displayed on their surfaces. Thus, infection is limited and soon aborted. These all are complex processes that are caused by several of cytokines, lymphokines, and chemokines that must be produced by cells in correct amounts. Over- or underproduction causes the immune response to be either inadequate or harmful to the host. Viruses counteract these processes in a variety of ways, most of which have been discovered and characterized only during the last 15 years. Among them are the following: Viruses blunt the effects of interferon by several different mechanisms. Some viruses synthesize proteins with affinity for double-stranded (ds) RNA, so that interferon-induced enzymes are not activated. Others synthesize RNA molecules that mimic ds RNA and bind to the enzymes that should be activated, which prevents real ds RNA from binding to the enzymes. Others are immune to the interferon-induced inactivation of the host's protein-synthesizing machinery; and others still encode "soluble" interferon receptors that reduce the intracellular concentration of free functional interferon molecules. Some viruses synthesize extra lymphokines, which causes various components of the immune system to overreact. Others synthesize proteins that bind lymphokines and prevent them from functioning. Andothers still interfere with the generation of functional lymphokines, the result being that functional T and B cell formation is prevented. Viruses defend themselves against the killing of infected cells. They do this either by synthesizing a protein that binds TNF (tumor necrosis factor), which targets infected cells for CTL attack, or by interfering with the formation of major histocompatibility complex (MHC) Class I antigens that function in the display of viral protein fragments on the cell surface, thereby targeting them for CTL attack. Such interference itself occurs through three distinct mechanisms-interference with the synthesis of MHC antigens, interference with the ability of these MHC antigens to combine with and "display" viral protein fragments, and interference with the transport of MHC class I molecules to the cell surface. Some viruses elaborate cytokine-like growth factors that cause infected cells and their immediate neighbors to multiply. Growing cells contain larger amounts of factors necessary for maximal virus multiplication; thus, the elaboration of these growth factors enhances and accelerates virus multiplication. Some viruses encode enzymes that synthesize steroid hormones; the extra amounts of such hormones cause immunosuppression and reduction of inflammation and therefore enhance virus growth and reduce the efficiency of virus clearance. Some viruses synthesize proteins that block the activation of complement, which damages the surface membranes of infected cells and the envelopes of viruses. Thus, we have learned a great deal concerning the mechanisms by which host cells repel and eliminate viral infections, and how viruses counteract these mechanisms. So far, about 20 genes are known to be involved in this process; there could well be between 50 and 100. Most of those known so far are utilized by the largest viruses, the poxviruses and the herpesviruses and, to a lesser extent, the adenoviruses. Highly lethal viruses with much smaller genomes, such as the flavivirus yellow fever virus or the arenavirus Ebola virus, do not encode proteins that appear to function via any of the mechanisms defined previously. Identifying host defense-neutralizing functions of the proteins encoded by these viruses will likely be far easier if more were known about cellular defense mechanisms. Further study of smallpox virus pathogenesis can provide that information. Without it, we would be looking for the equivalent of a needle in a haystack. That is the case for the virus that is currently the No. 1 public health problem worldwide, namely HIV. It would be fascinating to study the molecular pathology of smallpox virus isolates with different degrees of virulence. The major problem in this regard is neither the danger of working with infectious smallpox, nor accidental escape of infectious virus. Vaccinated personnel would carry out research, and several technical approaches could be taken to prevent an escape. But the fact remains that it is impossible to carry out this work in humans. A start could be made using SCID (severe combined immunodeficiency) mice. However, more detailed study of smallpox virus-human host defense mechanisms interactions will require additional model systems that are not currently available. But this lack of availability does not justify destruction of smallpox virus at this time. Molecular viral pathogenesis is only 15 to 20 years old; concluding that advances in the next 15 to 20 years will not yield a suitable experimental system would be a serious mistake. Photo: Bill Bamberger In summary, the symbolism of destroying the remaining stocks of smallpox virus is highly unlikely to influence anyone contemplating biological warfare or terrorism. The tenuous hope that it might exert such influence in no way outweighs the loss of a genome that has evolved to interact more specifically with human defense mechanisms than any other. It encodes too many unique reagents to warrant destruction. Wolfgang K. Joklik is chairman, emeritus, of the department of microbiology and immunology at Duke University Medical Center and the James B. Duke Professor of Microbiology, Emeritus. He can be reached online at joklik@abacus.mc.duke.edu.

The Remaining Smallpox Virus Stocks Are Too Valuable To Be Destroyed

Dec 8, 1996

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