The soriano award lecture emerging infections of the nervous system

JOURNAL OF THE

NEUROLOGICAL SCIENCES ELSEVIER

Journal of the Neurological Sciences 124 (1994) 3-14

R e v i e w article

The Soriano Award Lecture Emerging infections of the nervous system R i c h a r d T. J o h n s o n * Departments of Neurology, Molecular Biology and Genetics, and Neuroscience, The Johns Hopkins University School of Medicine, Meyer Building 6-113, The Johns Hopkins Hospital, Baltimore, MD 21287, USA (Received 10 November 1993; accepted 13 January 1994)

Abstract

The epidemic of acquired immunodeficiency disease [AIDS] has focused interest on the origins of "new" infectious agents. Great plagues are well known from the distant past, but a number of novel diseases affecting the nervous system infections have emerged in recent years. The causes of such new disorders are diverse: whereas rapid mutations of microbes allow the evolution of truly novel agents, the appearance of new diseases is more often due to changes in human or vector populations or changes in societal mores that result in dissemination of preexistent microbes. Examples of recently emerging infections that involve the nervous system include the enterovirus 70 epidemics with poliomyelitis-like disease, the appearance of California virus encephalitis in the midwestern United States, the rapid spread of Lyme disease with its many neurological complications in the eastern United States, and the outbreak of bovine spongiform encephalopathy in the United Kingdom, in addition to the devastating epidemic of human immunodeficiency virus (HIV), which will cause nervous system disease in over half of those infected. As the world population increases and modern transportation brings us closer into a "global village" more new agents will emerge and more will be sustained. Knowledge of the molecular biology and ecology of the agents and awareness of how our actions can alter their behavior are our best defense.

Key words: AIDS; Human immunodeficiency virus; Measles; Enterovirus 70; Acute hemorrhagic conjunctivitis; Poliomyelitis; California encephalitis virus; La Crosse virus; Lyme disease; Borrelia burgdorferi; Bovine spongiform encephalopathy; Mad cow disease; Virus mutations; Viral epidemiology and ecology

1. Introduction The acquired immunodeficiency syndrome (AIDS) epidemic continues to expand throughout the world. Countries in sub-Saharan Africa are suffering immense burdens of health care, high death rates, and growing numbers of AIDS orphans. Countries in the Americas and Europe are experiencing a shift of AIDS from male homosexual and bisexual populations to injecting drug users and consequently increasing numbers of transmissions to women and newborns. Countries in Asia are observing rapid rates of seroconversion, particularly in South and Southeast Asia, where it is predicted that an epidemic will surpass that of Africa (Merson 1993). In the face of this growing onslaught,

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several questions are frequently asked by professionals and nonprofessionals alike: (1) Is this epidemic unique in history? (2) Where do "new" agents come from? (3) What will happen in the future? This lecture addresses these questions by examining the historical development of "new" diseases, in particular their origins and how they have been sustained, so that we can be better prepared to deal with epidemics in the future.

2. The past Some years ago a human virus appeared that was thought to have evolved from an animal virus possibly in Africa. People of the African continent and the Middle East were the first victims, suffering from virus-induced immunodeficiency and dying of pneumo-

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nia and diarrhea and less often an accompanying demyelinating disease of the brain and spinal cord. When the agent reached Western countries it caused great numbers of deaths. It was said to have been worse than smallpox. The agent was measles; the time was the 6th to 8th Centuries A.D. (Johnson et al. 1988). Some dispute this scenario, positing that measles occurred in ancient China and entered the Middle East along the silk routes. In either case, the typical exanthem of measles was not described by early Greek and Roman physicians. The first convincing description of measles was by Abu Beer, known as Rhazes of Baghdad, who dates its appearance in the Arab world to the 6th century (Mead 1747). Although European descriptions of disease during the early middle age are scanty, it appears that measles spread across the Pyrenees into France with the Saracen invasion of the 8th century (Rolleston 1937). Measles is the only human morbillivirus and appears most closely related to rinderpest of cattle. Measles virus has no animal hosts. The virus must be maintained in human populations, even though measles virus infections confer lifelong immunity. Calculations of incubation period, efficiency of transmission, and interval of infectivity show that measles needs an interactive human population of more than 200 000 people to be sustained (Bartlett 1957). In early millennia a virus such as measles might have caused a brief epidemic but then would have disappeared. Measles also was the first recognized cause of a virus-induced immunodeficiency syndrome. Since the 18th Century measles had been associated with dissemination of tuberculosis. In 1908 von Pirquet documented that tuberculin-positive children became tuberculin negative for several weeks following the acute exanthem. During this period, opportunistic infections occurred causing increased mortality. Measles was not only the first, but also the most severe cause of virusinduced immunodeficieney before recognition of AIDS in 1981. Indeed, measles still causes over a million deaths per year (Asaad 1983), a number of deaths that will only be surpassed by infections of the human immunodeficiency virus (HIV) in the next few years. The history of pestilence has many examples of great plagues. Some, such as the great plague of Athens, the English sweats, and, in this century, von Economo's disease have erupted and disappeared. Some, such as syphilis have arisen and become attenuated. Others, such as measles, have appeared and remain with us (McNeill 1976).

3. The origin of new diseases

Emergence of a new disease can occur as a result of a mutational change and the evolution of a new

pathogenic agent or a minor genetic alteration that increases the virulence of an existing agent in human populations. Fortunately most significant mutations are lethal and growth in alien hosts attenuates virulence (Kilbourne 1991), but these generalizations are not always true. Alternatively, a new disease may appear simply because of a new encounter of humans with agents previously unrecognized in the environment. Most often, emerging diseases represent the increased dissemination of an agent due to transfer to new hosts or vectors or due to environmental changes that enhance its spread (Kilbourne 1990; Lederberg et al. 1992). Since bacteria have exponential growth rates and generation times of hours, the opportunity for mutational changes are vastly greater than they are in humans, which explains the rapid evolution and selection of drug-resistant strains of bacteria and possibly the appearance of the changing virulence of some bacterial infections. Viruses with rapid replication of millions of progeny have far greater potential for genetic variation. Viruses, however, are obligate intracellular parasites and cannot remain active in soil as can many bacteria and fungi. Therefore, a host population must be large enough to maintain a virus. For exampie, neolithic man, who lived in small communities and had only rare contact with other communities, could not have sustained most human viral infections. A few human DNA viruses were maintained by the strategy of latency. It has been proposed that DNA viruses such as herpesvirus evolved during the neolithic period; in early village populations reactivation of infection in the form of a herpetic blister or shingles years later could reintroduce the virus into a subsequent naive generation (Hope-Simpson 1965). RNA viruses are more common causes of infection in animals and humans than are DNA viruses and are the major causes of emerging diseases. Mutational rate during replication of DNA is approximately 1 error per 10 9 base pairs. In contrast, RNA is copied with much less fidelity because of the lack of proofreading enzymes; the error rate in replication from RNA to RNA is approximately 1 error per 104 base pairs, or about 100000 times greater than the mutational rate for DNA (Holland et al. 1982). Most RNA viruses are maintained in animal populations, and humans are only chance hosts as in the case of rabies, the arthropod-borne viruses or arenaviruses. As human populations have expanded, however, some RNA viruses have evolved that can be sustained as purely human parasites; among these are the picornaviruses, the influenza viruses, and the paramyxoviruses such as measles (Table 1). In addition to genetic changes, societal changes enhance both the evolution and the spread of neurotropic agents. The most important of these factors is the

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Table 1 Mechanisms for viral survival in host populations

4. Recent examples of emerging diseases

Virus

Mechanism

DNA viruses

Latency and activation after new nonimmune hosts born Seldom cause fatal disease (host survival)

4.1. The abrupt world epidemic of hemorrhagic conjunctivitis

RNA viruses Arboviruses Zoonotic viruses Human viruses Picornaviruses Influenza Measles Retroviruses HIV 1 and 2 HTLV-I

Mutation/spread in animal populations Mutation/spread in animal populations Mutations which supply new viruses Mutations and reassortment allows reinfection "New" virus that requires large human populations Latency and high mutation rate Additional low transmissibility, long incubation period, and long infectivity period All of above and low disease penetrance

Modified from (Johnson 1993b).

increasing global population which sustains viruses. The other dominant factor that enhances the maintenance and dissemination of agents is the greater degree and speed of human contact. In the original example of measles, a span of about 200 years appears to have passed before the virus crossed from the Iberian peninsula to the south of France. Because of a short incubation period and high infectivity, cycles of human infection had to occur during the traverse of the Pyrenees in order to sustain the virus. This transport had to await the massing of the Saracen army. Today a similar virus would cross the Pyrenees in hours. Today a new agent evolving in the most isolated village can reach our respective communities in a few days - within a single incubation period. In addition to the increasing population and the functional shrinking of our global village, many changes in social mores alter the spread of viruses (Table 2). Increased sexual contacts have recently enhanced the spread of herpes simplex virus, type 2, and HIV. Agricultural clearing has introduced rodent viruses as new epidemic diseases such as Lassa virus in Africa, 3unin virus in Argentina, and the recent appearance of Guanarito virus, the virus causing Venezuelan hemorrhagic fever (Salas et al. 1991). The global movement of animals poses the ever present danger of spread of a variety of bacteria, viruses, and parasites. Medical practices including blood transfusion, immunosuppressive therapy, and organ transplants from infected donors have lead to the transmission of agents and use of antimicrobial drugs has exerted pressure for development of resistant mutants. As discussed in the following examples, a combination of these genetic and societal changes may lead to the emergence of new diseases of the nervous system.

In the summer of 1969 a sudden epidemic of hemorrhagic conjunctivitis characterized by distinctive subconjunctival hemorrhages and conjunctival swelling occurred in Accra, Ghana (Chatterjee et al. 1970). Since the outbreak coincided with the Apollo 11 Mission landing on the moon, the local population dubbed the illness "the Apollo disease" with some implication that its emergence was nature's retribution for the lunar intrusion. During the subsequent year, the epidemic spread across to East and North Africa, to India, Thailand, Hong Kong, Indonesia and up to Japan; small outbreaks also were observed in various sites in Europe. Sporadic outbreaks occurred between 1972 and 1979, but none were of the magnitude of the early epidemic. A decade after the first epidemic, hemorrhagic conjunctivitis reappeared in epidemic form in south India. For the first time the epidemic spread to the Americas, initially to Brazil, then along the north coast of South and Central America to the United States where small numbers of cases where seen in Key West and North Carolina (Yin-Murphy 1984). After another decade passed, a third outbreak occurred in American Samoa (Bern et al. 1992), but the epidemic spread of the previous two waves has not been observed (Fig. 1). The initial two epidemics were of neurological interest, because about 1 per 10000 patients in India also developed an acute lower motor neuron paralysis that resembled acute poliomyelitis (Bharucha and Mondkar 1972; Wadia et al. 1972). Similar paralytic disease was also reported in Formosa and Japan. The neuroviruTable 2 Societal changes that enhance the evolution and spread of neurotropic agents Providing an adequate pool of susceptibles Altering forms of human or animal contact Societal mores

Medical practices

• Increasing global population • Increasing human contacts (travel)

• Increased sexual contact • Day care with early exposure • Alterir~.; woods for suburbs and recreation • Agricultural clearing or irrigation • Global movement of animals and animal products • • • •

Blood transfusions Immunosuppressive therapy Organ transplants (infected donor) Antimicrobial drugs (encourage resistance)

Modified from Johnson (1993b).

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lence of these strains of virus was further established when they were shown to cause paralytic disease in monkeys (Kono et al. 1973). The virus was recovered from conjunctival swabs, identified as an enterovirus, and was designated enterovirus 70. It is assumed to have originated from a human enterovirus, although some have questioned whether it might have had an animal origin, because this virus has a wider host range in cell culture and grows at lower temperatures than do other human enteroviruses (Tanimura et al. 1985; Miyamura et al. 1986). The explosive epidemic potential is related to its unusual route of spread. Although an enterovirus by molecular structure, this virus does not cause an enteric infection and is not even isolated from stool as other enteroviruses are; in contrast, it spreads from hand to eye, similar to some adenoviruses. This change in mode of spread results in an abbreviated incubation period and more rapid dissemination, particularly in densely populated areas. Enterovirus 70 virus has been shown to undergo rapid mutational changes. By oligonucleotide mapping, isolates recovered over time show a 0.4% (or 32 base pairs) shift per year (Miyamura et al. 1986). This rapid mutational rate is of particular importance for a virus that spreads rapidly and has been thought to have outstripped the susceptible population. In the recent outbreak in American Samoa, however, reinfection was

seen in a population that had been affected by a prior epidemic, although the rates of clinical disease were lower. Previous infection appeared to give only partial protection (Bern et al. 1992). Enterovirus 70 represents a newly evolved RNA virus that causes a new clinical disease with neurovirulence that resembles that of polioviruses. The virus also has assumed a different mode of spread which leads to a changed epidemiological pattern. Each epidemic wave has abated, and it is uncertain whether the population of the world is sufficiently large to sustain this virus between outbreaks or whether an accumulation of mutational changes will allow new major outbreaks in previously exposed populations. Since neurovirulence neither favors nor constrains viral survival, this property may diminish or accentuate unpredictably over time. 4.2. New mosquito-borne encephalitis in the United States

In the summer of 1963 a child died of encephalitis in La Crosse, Wisconsin, and a virus was recovered from the brain (Thompson et al. 1965). This virus proved to be a strain of California virus, an agent originally recovered from mosquitoes in California, but previously unknown in the midwestern United States and unknown as a cause of fatal encephalitis. Since 1963, over 2000 cases of encephalitis due to the La

1991

Fig. 1. Global spread of enterovirus 70. The first epidemic in 1969 and 1970began in West Africa, spread across Africa to Europe and Asia. The second wave began in South India in 1970and spread across Asia and into the Western Hemisphere. An isolated outbreak occurred in Samoa in 1990.

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Crosse strains of California virus have been reported with 90% occurring in Ohio, Wisconsin, Minnesota, Illinois, Indiana, and Iowa (Fig. 2). Of these patients, 90% are under 15 years of age. Most recover without sequelae and fatalities, such as that of the index case, are rare. Although infection with this virus is prevalent in adults who live or work in woodlands, it is very rarely associated with encephalitis, whereas infection in children under 15 years of age leads to reported cases of encephalitis in about 1 in 500 to 1500 infections (Grimstad et al. 1984). California virus was originally isolated in 1952 in California and a moderate seroprevalence of antibody against the virus had been found in Kern County, California, despite the rarity of any clinical disease (Reeves et al. 1983). The neurovirulent variant of virus in the Midwest appears to be spread primarily by the Aedes triseriatus mosquito which breeds in woodlands primarily in the dark, stagnant water in tree holes. Squirrels, chipmunks, and other small woodland .animals are the predominant vertebrate hosts. Birds, which are the major vertebrate host of most mosquito-borne viruses, are not susceptible even to experimental infection. Children, therefore, become infected primarily by playing in wt~oded areas. This exposure has increased as modern suburban development has encroached into these areas, particularly since recent development of housing tracts has avoided the clearing of trees. In addition, the custom of abandoning old tires in the backyards has provided collections of dark, stagnant

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water that the short-flighted Aedes mosquito has found an attractive habitat; thus, parents are unwittingly exposing children to infection within their yards. In Cleveland, Ohio, serosurveys of children in schools in 1967 showed a prevalence of antibody of about 2.4-3.7% in established housing areas and 5.5% in semirural areas. On the other hand, examination of sera obtained during poliomyelitis vaccine trials in the early 1950s failed to show antibody against the California group of viruses in any subjects (Johnson et al. 1968). Although this suggested that the virus might be new to the region or to have exposed humans only recently, a serosurvey in Indiana showed seropositive rates climbing steadily with age, suggesting longterm human contact with the virus (Grimstad et al. 1984). The new strains of California virus with greater neurovirulence that emerged in the midwestern United States in the 1960's may have been longstanding, but newly recognized, inhabitants of the area. Alternatively, the neurovirulent La Crosse strain may have been derived from new mutations or have represented new entry of the virus into areas accessible to children. Further, this could have been the result of a change of the mosquito vector from one that failed to bite humans to the Aedes species that will feed on humans. Clearly, greater human contact with the breeding sites by placing houses in wooded areas and leaving old tires as breeding sites has increased the exposure of toddlers and young children. Emergence of this new disease may represent a new recognition or genetic alter-

l

ll Fig. 2. Distribution of California encephalitis in the United States. Cases reported to the Centers for Disease Control between 1964and 1991 are shown.

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ation of the virus, a change of vector or vector-host cycle, increases in the interface of human activity with the virus habitat, or, most likely, a combination of several of these factors. Changes of vectors can occur. Recently, the Asian tiger mosquito, Aedes albopictus, was imported into the United States from Southeast Asia in used automobile tires (Francy et al. 1990). This mosquito is rapidly becoming established in urban and suburban regions of the southeastern and midwestern United States. Aedes albopictus has been shown experimentally to be an effective vector for California viruses, it feeds on small mammals, and it aggressively bites humans. If La Crosse strains of California virus were to be established in this vector, larger numbers of children living in more urban settings over a wider geographic area may suffer from California encephalitis in the future.

4.3. The emergence of Lyme disease in the Northeastern United States In the autumn of 1975 an artist from Lyme, Connecticut, collected 35 mysterious cases of unexplained arthritis in her community, including members of her own family, and presented them to Dr. Allen Steere at Yale (Aronowitz 1989). This appeared to be a new disease in three contiguous communities along the East bank of the Connecticut River. The cases resembled juvenile rheumatoid arthritis and clustered seasonally between June and September. Steere observed that the disease often began with a

characteristic skin lesion, erythema chronicum migrans, which had long been associated with inflammatory neurological disease in Europe. Headache, stiff neck, myalgia, arthralgia, and lymphadenopathy often accompanied the rash. Weeks or months later encephalomyelitis, radiculitis, and peripheral neuropathies sometimes developed, as well as myocarditis and frank arthritis (Steere et al. 1983). Early epidemiological studies in the Connecticut River valley showed the incidence of the disease to be 2.8 per 1000 east of the river and 0.1 per 1000 west of the river (Steere et al. 1978). Furthermore, a species of ixodid tick was found primarily to the east of the river and 13 times more abundant on white-footed mice and 16 times more abundant on white-tailed deer on the east than on the west side (Wailis et al. 1978). The species of tick, Ixodes scapularis (I. dammini) had recently been detected and was thought to be making a comeback from near extinction (Spielman et al. 1979). The assumption was made that a tick-borne virus caused the disease, but serological and virus-isolation studies proved negative. By 1978 empiric evidence had accumulated that antibiotics were effective in treatment, suggesting a bacterial cause. In 1982 Burgdorfer at the Rocky Mountain Laboratory studied a sample of ticks and identified the spirochete of Lyme disease, now named in his honor Borrelia burgdorferi (Burgdorfer et al. 1982). The spirochete has been recovered from blood, cerebrospinal fluid, and joint fluids of patients and from the skin at the erythematous outer rim of the skin lesion (Steere et al.

i m

I 1oo[ Fig. 3. Distribution of Lyme disease in the United States. Cases reported to the Centers for Disease Control in 1989 and 1990 are shown. Cases were reported from 46 states, but, in the West, the disease has a different vector and cycle.

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1983). The same species of Borrelia has been associated with the disease in Europe and the western United States, but in these sites the spirochete is transmitted by different species of ticks. The epidemic of Lyme disease in the eastern United States continues to burgeon, both in patient numbers and geographic area (Fig. 3). The spirochete is clearly not new; the disease it causes has been recognized in Europe for almost 100 years. The dramatic surge of disease in the United States does not appear to be due to new introduction or a shift in virulence of the agent, but in the dramatic increase in the vector and its natural hosts (Barbour and Fish 1993). A century ago most of New England had been deforested for agriculture, and deer were hunted for venison. However, a shift in land use patterns has occurred; small farms were closed and reforestation accompanied suburban housing development. There is now four times as much woodland as there was 100 years ago; this secondary growth is choked with undergrowth and has no pr.edators large enough to control deer populations (Lederberg et al. 1992). Consequently, vast increases in the deer and deer-mouse populations have occurred. In turn, this has produced an explosion of the tick population, and this formerly "endangered species" now enjoys a broad geographical distribution that continues to expand every year. 4.4. Bovine spongiform encephalopathy (mad cow disease) in the United Kingdom

In the autumn of 1986 a dairy farmer in Kent, England, noted strange gaits, anxious behavior, and unusual aggression in several cows in his herd. Subsequent examination of their brains showed spongiform changes resembling those of scrapie in sheep. In retrospect, the disease probably began among dairy herds in 1985, but the recognition of the zoonotic of bovine spongiform encephalopathy or "mad cow disease" officially began with examination of these few cows in November 1986. By the end of 1992 over 92000 cows had been lost to the disease on 25 000 different farms in the United Kingdom. The disease also was reported in dairy cattle in Switzerland, France, and Northern Ireland and in five species of captive exotic ruminants. The disease had developed in cattle shipped from Britain to Oman, the Falkland Islands, and Denmark. In addition, a number of domestic cats have developed the disease as well as a puma and a cheetah in zoos. There is no evidence of animal to animal spread of this disease in cattle, exotic ruminants, or cats. The disease appeared to originate from some common source with a long incubation period. In ruminants, the disease appears to be related to supplementation of the diet with meat and bone meal obtained from commercial rendering plants, and in domestic cats the

t;

disease occurred in those fed with cat food containing products of the same rendering process. It is assumed that the processing of scrapie-infected sheep contaminated the meat and bone meal fed to cattle; in turn the carcasses and offal of infected cattle returned to the rendering process amplified the epizootic. The incubation period of the disease in cattle appears to be 2.5-8 years. Not only are more bone meal supplements given to dairy herd calves, but beef cattle are often killed between 12 and 36 months of age; therefore, the disease is confined largely to the dairy herds. Bone meal from rendering plants has been used as supplementation for young calves for many years. The sudden new epizootic appears to have resulted from recent changes in the rendering industry. In an effort to conserve energy during the oil crisis of the 1970s, many rendering plants changed from batch rendering to continuous rendering, which might result in unequal heating of all material. Probably of greater importance was the fall of the tallow market in the beginning of 1979, and consequent inclusion of greater amounts of fat in meat and bone meal and the removal of hydrocarbon solvents from the process, solvents that might have been important in inactivating the scrapie agent (Wilesmith and Wells 1991; Wilesmith et al. 1991). There is no evidence to date that this crisis in the dairy industry has led to transmission of disease to man, but kuru and Creutzfeldt-Jakob disease demonstrate that man is susceptible to spongiform encephalopathies. Kuru was transmitted by ritual cannibalism; Creutzfeldt-Jakob disease is transmitted by inheritance in 10-15% of cases, by transplants or human cell extracts administered by physicians in a very small number, and by unknown means in a great majority. Concern that these human diseases may have originated from sheep scrapie, the first recognized and prototype spongiform encephalopathy, resulted in intense study for many years, and provided conclusive evidence that there is no geographic concordance of scrapie in sheep with Creutzfeldt-Jakob disease in man. Indeed, continents in which scrapie does not occur, such as Australia, have approximately the same incidence of Creutzfeldt-Jakob disease as do countries with high rates of sheep scrapie. There is also no correlation between the eating of mutton and the disease nor between individuals in any particular occupation, such as butchers or animal handlers, with the occurrence of Creutzfeldt-Jakob disease (Bolis and Gibbs 1990). Thus, most people eat lamb and mutton, even rare lamb, without concern, even though they are aware that usual cooking Would not inactivate the scrapie agent. Concern with bovine spongiform encephalopathy occurs because this spongiform encephalopathy agent has been widely transmitted orally , a cows. Transmission from cows to mice, goats, sheep and mink by the oral route has been possible, but in

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other respects the biological characteristics of the agent are not distinguishable from usual scrapie. Nevertheless, the question remains, does this represent a variant of the agent which has greater facility to infect by oral ingestion? The recognition of bovine spongiform encephalopathy in the United Kingdom led to a ban on ruminant protein in ruminant foodstuffs, a ban of specific bovine offal from products for human or animal consumption, and strained relationships in the European Economic Community. In Britain fear was fanned by the press. The development of spongiform encephalopathy in house cats after eating pet food brought the disorder closer to home, and, following those reports, 26% of Britons stopped eating beef and over 2000 schools in Britain banned the use of British beef in the school lunch programs. The government initially denied "any possibility of human health risk," yet their establishment of a registry of Creutzfeldt-Jakob disease seemed to legitimize public concern. Although the epizootic of bovine spongiform encephalopathy appears to have reached a peak and the rate of the disease in cows more than 2 to 3 years of age is declining (Wilesmith and Ryan 1993), this story may not yet be over. Concerns continue about the prior inclusion of bovine serum in pharmaceuticals and vaccines administrated Dy injection. Although it is highly unlikely that man is involved (Gibbs et al. 1992), the mad cow disease episode presents a chilling demon-

stration that minor changes in the food chain can introduce agents into new hosts.

5. Human immunodeficiency virus (HIV)-associated neurological disease In the summer of 1981, unusual clusters of cases of Kaposi's sarcoma and pneumocystis pneumonia were reported in otherwise healthy, young gay men (Centers for Disease Control 1981a,b). This represented the first recognition of AIDS. Certainly no one could have predicted that these observations heralded an epidemic that would tear the fabric of international society, and an epidemic of nervous system disease that would eclipse all ~:ior infections of the nervous system in both number of cases and diversity of syndromes. In retrospect, widespread infections had been occurring among both gay populations in North America and in urban heterosexual populations in Africa in the 1970s. The disease was associated not only with sexual contact but with intravenous drug use, transfusion of blood and the delivery of blood products, and transmission to the neonate; these striking parallels to the epidemiology of hepatitis B virus suggested a viral etiology. HIV was recovered in 1983 (Blattner 1991). During those early years of the AIDS epidemic, neurological interest was limited to opportunistic infection of the nervous systems such as unusual manifesta-

Fig. 4. Global distribution of 13 million cumulative HIV infections in adults as of mid-1993. Data from the World Health Organization modified from Merson (1993).

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tions of toxoplasmosis and cryptococeosis and the high rate of cerebral lymphomas. Then in 1985 virus was isolated from the brain, spinal fluid, and peripheral nerve of AIDS patients with neurological diseases (Ho et al. 1985; Levy et al. 1985); HIV RNA was demonstrated in microglial nodules in brains of HIV-infected individuals; Southern blot analysis showed HIV DNA at higher levels in brain than in lymph node, spleen, or lung (Shaw et al. 1985); and finally, increased levels of HIV antibody were found in cerebrospinal fluid indicating intratheeal synthesis of antibody (Resniek et al. 1985). In the same year, sequence analysis showed that HIV was not a member of the family of tumor-producing retroviruses like HTLV-I, but was a lentivirus (Gonda et al. 1985), a subfamily of retroviruses all of which cause persistent nervous system infection and subaeute encephalitis. These findings led to the realization that HIV caused primary disease of the central nervous system. Was this a rare nervous system invasion occurring in terminal patients or was it a common infection occurring early during asymptomatie infection? Prospective studies of populations of gay men at risk demonstrated that in the majority of individuals spinal fluid obtained early after seroconversion and long before the development of symptomatic AIDS showed evidence of infection by recovery of virus, inflammatory responses or presence of oligoclonal antibody (MeArthur et al. 1988). Therefore, most of the 13 million people now infected with the HIV already have central nervous system infections, and HIV is now the commonest central nervous system infection in the world (Fig. 4). Furthermore, the majority of those infected will develop neurological disease - dementia with encephalopathy, paralysis with myelopathy, or pain with peripheral neuropathies as well as a variety of other diseases, albeit with lower frequency (Johnson et al. 1988b). Over the next decade, as the number of infected persons doubles and most of those who are seropositive develop disease, these neurological complications of HIV infection will become some of the most prevalent neurological diseases of humans. Many questions about the pathogenesis of neurological complications of HIV remain unanswered. How does the virus invade the nervous system? Are there specific neurotropie a n d / o r neurovirulent strains of HIV? Are only ceils of the macrophage lineage infected in the human nervous system? Is the amount of "virus burden" related to development or progression of neurological disease and is the disease mediated by viral proteins, excitotoxins, eytokines, or some other mechanism? Do different syndromes have different mechanisms of pathogenesis? When and how do antiviral agents modify the course of these diseases? (Johnson 1993a). We can assume that HIV, like other RNA viruses,

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originated sometime in history from an animal virus, but it is not necessarily a new virus of humans. Indeed, this virus could have existed in small villages somewhere in the world for centuries. The long incubation period is not a latent period. Although the virus is latent in some cells, an ongoing production of infectious virus continues in others, so that the asymptomatic infected person is infectious over a 7-10-year period between initial infection and the development of clinical disease. In village life the premature death of a small number of persons with this disease might go unnoted. Infection rate would be maintained only by ongoing sexual infidelities. If these did not occur, the virus in that population simply would disappear. Indeed, irrespective of style or frequency of sexual activities, if these involve only a single partner, even today's fullblown AIDS epidemic would disappear from the world in a single generation. Studies of villages in rural Zaire have shown a seropositive rate below 1%, which has not increased over the last decade despite the large increases of seropositivity and AIDS in urban areas (Nzilambi et al. 1988). The introduction of needles and syringes into Africa in the 1950s for immunization programs and antibiotic administration may have contributed to early spread of HIV (Karpas 1990). Urbanization and greater sexual license more recently have contributed to the epidemic in Africa, and spread has been enhanced by the growing prevalence of other sexually transmitted diseases that increase the risk of HIV transmission to both males and females (Simonsen et al. 1988). In North and South America as well as Europe, the initial spread was largely among those h~.mosexual and bisexual men who followed a more ~romiscuous lifestyle and among those who shared needles during drug use. Retroviruses have a unique strategy for survival in animal populations. They combine the capacity of latency characteristic of DNA viruses with high mutational rates common to RNA viruses (Table 1). Retroviruses contain a reverse transcriptase, and, after entering the cell, a DNA copy is made of the genomic RNA. This proviral DNA can integrate in the host cell and remain latent without symptoms for a lifetime. For lentiviruses, however, virus continues to replicate at low levels assuring transmission of disease. As in RNA viruses the mutation rate is high, and mutations accumulate throughout the long incubation period. This allows for great variations of viruses, and evolution of viruses that may cause different clinical syndromes, that will not be neutralized by antibodies evoked by vaccines, and that acquire resistance to antiviral drugs. Such a virus poses a formidable adversary. Since 1981 the speed of research from recognition to disease, recovery of virus and its molecul~.r characterization, and development of effective antiviral drugs to testing of multiple candidate vaccines is unprece-

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dented. We even know how to prevent the disease check blood supplies and products, use clean needles and syringes, limit sexual partners and use condoms. Yet the latter mree require changing human behavior, the most difficult challenge a microbial threat might pose.

6. The future New agents will continue to evolve through genetic mutations, such as enterovirus 70, which acquired new pathogenic potential and a new mode of rapid dissemination; however, even with the increasing human population the virus may eliminate the nonimmunes before sufficient new mutations allow reinfection and persistence of the agent in human populations. Other agents such as California encephalitis virus and the spirochete of Lyme disease will emerge because of minor mutational changes, increases or changes of vectors or intermediate hosts or alterations of human behavior that increase the interface of human with microbial habitats. Also the unexpected will happen, as exemplified by bovine spongiform encephalopathy where business decisions unwittingly had an impact on the food chain and introduced the agent into new hosts. Finally, agents such as HIV will evolve that seem to circumvent the rules of engagement and may defy control - agents that can ~.stablish latency, maintain long term infectivity, and can mutate at rates that overcome host immune defenses and pharmacological interventions. Man has made remarkable achievements in controlling nature, other animal species, and to some extent, his own behavior. Nevertheless, past successes in the development of antibiotics to control infections and application of vaccines to eradicate smallpox and to eliminate indigenous wild polioviruses from the Western Hemisphere do not prove our invincibility. As Lederberg (1988) has written, "We have too many illusions that we can, by writ, govern the remaining vital kingdoms, the microbes, that remain our competitors of last resort for domain of the planet. The bacteria and viruses know nothing of human sovereignties. In that natural evolutionary competition there is no guarantee that we will find ourselves the survivor." Some commentaries on the emergence of new infectious agents clearly imply that they arise because of human wickedness (Epstein 1993; Gibbons 1993). The sexual spread of HIV has reinforced this judgmental posture as has the spread of agents resulting from deforestation or the pollution of waterways. This implies that emergence of new agents could be curbed by political or ecological "correct thinking." Yet the campers in the high country who transmitted Giardia parasites to beavers and polluted the pristine waters of the subalpine Rockies were not wanton polluters. The

reforestation of the northeast United States and the environmental movements that limited deer hunting and led to the explosion of ticks and Borrelia infections were not motivated by ecological irresponsibility. Indeed, many of what we consider good acts in society may be exploited by our microbial adversaries. Provision of day care and schooling for the young has led to the early exposure to measles and spread of picornaviruses. Recreational activities increase exposure to arthropod-borne viruses, malaria, the plague bacillus, and rabies. Irrigation projects to provide better food supplies have led to the spread of Western encephalitis virus in the United States, Japanese encephalitis virus throughout Asia, and Rift Valley fever virus in Africa. Development of cooperative economic communities has facilitated the international movement of bovine spongiform encephalopathy in Europe and might spree',' Venezuelan equine encephalitis in the Americ,~:. Modern medical advances, such as organ transplants, have led to transmission of disease, and nosocomial infections, and antimicrobial drugs have led to the evolution of resistant strains of bacteria and viruses (Table 2). Changing our political thinking is not the solution; knowledge is. We must arm ourselves with the knowledge of the genetics of microbes, develop a deeper understanding of their ecology, and acknowledge the fact that no matter how we alter our common habitat, the microbes, with their astonishing genetic potential, can exploit our every move. Acknowledgement Supported by PO-1-NS 26643 from the National Institute of Neurological Diseases and Stroke, The Nat!onal Institutes of Health.

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