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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Chapter 57Monkey B virus

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Department of Biology, Georgia State University, Atlanta, GA, USA

Introduction

B virus (Cercopithecine herpesvirus 1, herpesviridae), an alphaherpesvirus endemic in macaque monkeys, has the unique distinction of being the only one of nearly 35 identified non-human primate herpesviruses that is highly pathogenic in humans. B virus has been positively linked with more than two dozen human deaths since the first report describing it in 1933, five of those in the last 12 years, following exposures involving macaques in during acute B virus infection. B virus, unique among the non-human herpesviruses, is included in this volume because it is distinctively neurotropic and neurovirulent in the foreign human host inadvertently exposed by handling macaque monkeys generally used in biomedical research. Untreated B virus infections in humans result in an extremely high mortality rate (∼80%) and, consequently, present unique and potentially lethal challenges for individuals handling macaque monkeys or macaque cells and tissues. Infection in humans is associated with breach of primary skin or mucosal defenses and subsequent contamination of the site with virus from a macaque or cells or tissues harvested from this animal. Fomites, contaminated particulates or surfaces, can serve as source of virus as well. In one case, human-to-human transmission was reported and attributed to a shared tube of medication which resulted in contamination at a broken skin site with cream used to treat another patient’s bite wound. Later, the same patient autoincoculated one eye during manipulation of a contact lens. In 28 zoonotic cases occurring during the 1980s and 1990s out a total of 46 documented cases confirmed since 1933, 80% have survived infection with the advent of antiviral therapies in contrast to 80% mortality reported in untreated patients. Timely antiviral intervention is an effective means of reducing B virus-associated morbidity and preventing a fatal outcome.

History

The first case to appear in the medical literature was described as follows. A laboratory worker accidentally bitten by a monkey, apparently recovered from the bite, but immediately afterward fell ill of a febrile disease with progressive symptoms of ascending myelitis and died 15 days after the first symptoms of involvement of the central nervous system (CNS). The gross and histological picture included areas of softening in the mid brain and widely diffuse areas of perivascular lymphocytic infiltration. While the brain of this individual was contaminated with a coliform bacterium, it yielded, on rabbit brain passage, a bacteriologically sterile tissue cell culture isolate that killed rabbits with invariably characteristic neurologic symptoms and also caused an exaggerated skin lesion that was subsequently followed by ascending myelitis and death. The virus present in the brains of these animals was thoroughly compared with known strains of herpes viruses by crossed immunity reactions which will be elsewhere described. This agent produced lethargic encephalitis in Cebus but not in rhesus monkeys.

Gay and Holden (1933) reported an ultrafiltrable agent, similar to herpes simplex virus, recovered from this brain tissue as received from Albert Sabin. They initially designated the isolate “W” virus, noting that it caused similar disease in rabbits infected by either intradermal or intracranial routes, but a rhesus macaque exposed to virus showed no illness. Within a year of these first reports by Gay and Holden, Albert Sabin independently reported an ultrafilterable agent that he identified as “B” virus from tissues of this same index patient, naming the virus by using the initial of the last name of the patient. These studies were expanded with the observation that B virus, deadly in this patient, caused disease strikingly different from HSV. Sabin described the case as follows: in 1932, a young physician (WB) was bitten by a macaque monkey and later developed localized erythema at the site of the animal bite. This apparent localized infection was followed by lymphangitis, lymphadenitis, and ultimately a transverse myelitis, with the demise of WB ascribed to respiratory failure. At the time of WB’s death, tissue specimens were obtained for laboratory investigation.

The virus subsequently has been called B virus, herpes B virus, herpesvirus simiae, or Cercopithecine herpesvirus 1. The lethality of B virus infection in rabbits was described by Sabin (1934) who showed that infectivity was independent of route of inoculation. Experimentally infected dogs, mice, and guinea pigs, on the other hand, showed no susceptibility regardless of route of infection. Both Gay and Holden, as well as Sabin, observed that B virus induced immunological reactions in an infected host similar to HSV-1. The virus was noted also to share similarity with pseudorabies as well as with other viruses, including SA8 and two additional herpes non-human primate alpha-herpesviruses recently described, HPV-2, originally described as SA8 (Simian Agent 8)(Eberle et al., 1995) and Langur herpesvirus (J. Hilliard, unpublished data).

Twelve fatalities were identified by 1959 along with five survivors. Detection of antibodies in humans, in the absence of clinical symptoms but with a history of working with macaques, is unreliable; however, these tests early antibody could not discriminate between antibodies induced by HSV types 1 and 2 vs. B virus. Subsequently, with the development of more precise tests, Freifeld et al. (1995) observed a high risk population (n = 325) that antibodies were rarely, if ever, present in the absence of a history of clinical symptoms. Following another fatal case, however, antibodies were found to be present in at least two coworkers and one additional individual with no previous history of HSV 1 or 2 (J. Hilliard, unpublished data). Two of the three reported a significant illness, describing symptoms commensurate with early stages of B virus infection nearly a decade earlier but with full recovery. These observations suggest B virus may reactivate and be responsible for maintenance of high antibody titers long after acute illness; however, there are too few cases to suggest with certainty that B virus reactivates in humans who survive acute disease.

Distribution in nature

All species of macaques appear to serve as the natural hosts of B virus. There are, in general, genotypic differences associated with B virus depending on the species of macaques from which it was isolated. There is an absence of strong evidence to suggest that there is a difference in the pathogenesic mechanisms of these different genotypes when they infect humans. The macaque host is found most often in the Asian wilds, but colonies of these animals have been exported to a number of other regions, for example, the Isle of Mauritius and Gibralter. B virus can also infect humans (1987, 1987, 1989; Benson et al., 1989; Artenstein et al., 1991), as well as other species of monkeys housed next to macaques (Loomis et al., 1981; Wilson et al., 1990). Other vertebrate species can be infected, including other non-human primates, but in such cases the infected animal serves as a foreign host and frequently succumbs to infection. N/P B virus transmission results from direct contact, whether from animal to animal, animal to person, person to person, or contaminated object to animal or person. There has been only one recognized case of human-to-human transmission observed in 1987 (Palmer, 1987; Weigler, 1992; Weigler et al., 1993).

B virus is highly prevalent in host natural performed reservoirs. Estimations of prevalence have been by a variety of investigators and techniques for both wild and captive macaque populations (Shah and Southwick, 1965; DiGiacomo and Shah, 1972; Kessler and Hilliard, 1990; Weigler, 1992; Freifeld et al., 1995; Sato et al., 1998). Transmission of infection correlates with onset of sexual activity, facilitating transmission of the virus among animals within a group (Weigler et al., 1995). Crowding of animals during transportation seems to accelerate the spread of infection within a community (Keeble et al., 1958; Keeble, 1960). A number of captive colonies worldwide are attempting to define and breed macaques free of B virus, but generally, due to the nature of the virus, antibodies are usually the only measure of prior infection. Investigators will be challenged greatly as they try to eliminate a virus that has coevolved with this host for nearly 30 million years!

As would be expected of an alphaherpesvirus infection in the natural host results is frequently associated with mild clinical signs, if any. B virus infection, however, can have serious consequences under certain immunosuppressive conditions, as observed by a number of investigators and reported by Chellman and colleagues (Chellman et al., 1992). Under these conditions, virus shedding from mucosal membranes can be documented easily by virus isolation in cell culture. In most infected animals, persistent, high antibodies throughout the lifetime of the host provide supportive evidence that B virus, as with HSV, reactivates periodically. N/P Virus can be reactivated in vitro (Boulter, 1975; Vizoso, 1975) from ganglia harvested from asymptomatic seropositve animals. In healthy animals, virus reactivation can be documented by recovery of virus from mucosal samples; however, virus is excreted for only short periods of time (Weigler et al., 1993; J. Hilliard, unpublished data). Collectively, these observations are not surprising in view of data derived from other alpha herpes viruses.

The virus

Isolation and growth properties of B virus

In 2003, the Department of Justice listed B virus as a Select Agent when it is outside of the natural host further restricting work with this virus, a potential tactical agent of terrorism. Because the agent is capable of causing death in up to 80% of untreated cases, the Center for Disease Control and Prevention (CDC) has undertaken the responsibility of defining agent summary statements for work performed with B virus. Isolation of virus is recommended in BL-3 containment laboratories while growth and propagation is strictly confined to BL-4 maximum containment facilities. Obviously, early work with this agent was done under far less stringent containment.

As noted, B virus was initially isolated from rabbit brain homogenates following fatal zoonotic infections. Within a decade after its discovery, chorioallantoic membranes or embryonated eggs were used for growth and propagation of B virus. By 1954, B virus was reported isolated from primary rhesus kidney tissue used for polio vaccine production. Virus was also noted to be present in rhesus central nervous system tissue. Shortly thereafter, monkey kidney and chick embryo were found to support in vitro replication of virus. In B cells, virus induces syncytial cells uniquely characteristic of this agent.

Following virus isolation, B virus was found to be relatively stable in cell culture media stored at 4 ℃. Long-term storage, however, required −80 ℃, not −20 ℃. These observations have been important for optimizing recoverability of virus from clinical samples to better understand the agent from both the macaque host and others, including humans.

B virus replicates to high titer in cell lines derived from Old World monkeys, particularly in Vero cells derived from African green monkey and vervet kidney cells. Rabbit kidney cells, BSC-1, and LLC-RK also support replication of B virus. Vero cells are an optimal cell line for isolation of virus from clinical specimens. Infected cells balloon, fusing into polykaryocytes that expand outwardly as more cells become infected. Eosinophilic, intranuclear inclusions (Cowdry type A bodies) are observed following fixation and staining of infected monolayers of cells, but inclusions are neither always observed in infected animals nor in some humans with zoonotic infection. As a result, intranuclear inclusion bodies should not be relied upon as a diagnostic marker. In the event this agent is inadvertently isolated in a BL-2 laboratory, cultures should be sealed and forwarded to a registered specialty laboratory that can handle this select agent safely and in accordance with federal guidelines.

In culture, B virus grows with kinetics similar to HSV (Weigler et al., 1993). Virus particles adsorb to cells, resulting in fusion and virus penetration of susceptible cells with suitable receptors. The nature of the cell receptors will be discussed in further detail later. Early in infection (3–4 hours), virus activity eclipses, but cellular responses can be detected by preliminary microarray analysis within the first hour post infection (Zao et al., unpublished data). Although host cell machinery is halted once virus enters the cell, innate immune responses of the cell post infection work presumably to counteract the virus. This, too, will be discussed in more detail later in this chapter. By 4 hours postinfection, DNA synthesis increases dramatically as does synthesis of polypeptides (Hilliard et al., 1987). Morphogenesis of the the virus is also similar to that of HSV, as shown by electron microscopy studies during the time course of infection (Ruebner et al., 1975). Within 6–10 hours after infection, infectious virions are detectable. By 24–28 hours postinfection, intracellular and extracellular virus levels plateau. Similar to HSV, B virus expresses sequential classes of proteins, i.e., immediate early, early, and late proteins (Hilliard et al., 1987). Homologous glycoproteins, as well as structural proteins, are encoded by the B virus genome (Slomka et al., 1995). Previous studies have characterized the antigenic relatedness of many of these proteins to those from HSV types 1 and 2, and to other non human primate alphaherpesviruses (Eberle et al., 1989; Hilliard et al., 1989).

The B virus genome

Two complete B virus genome sequences derived from cynomologus and rhesus monkeys, respectively (Harrington et al., 1992; Perelygina et al., 2003) have been published along with a number of partial sequence analyses (Bennett et al., 1992; Killeen et al., 1992). The total genome length has been calculated to be 156 789 base pairs for rhesus derived B virus and x bp for cynomolgus derived B virus.

B virus contains a double-stranded DNA genome of approximately 162 kbp. One strain of virus originating from a cynomologus monkey has been mapped and subcloned by Harrington et al. The genome contains two unique regions (Ul and Us) flanked by a pair of inverted repeats, two of which are at the termini and two internally located, an arrangement allowing four sequence-orientation isomeric forms. The overall size of the genome is slightly larger than HSV-1 (152 kbp) and HSV-2 (155 kbp). The guanosine:cytosine content of the DNA was calculated to be 75% based on the buoyant density of viral DNA. Eberle et al. published data which established the presence in B virus of gene homology to HSV-1 and HSV-2, gB, gC, gD, gE, and gG. Further examination of the sequences of the nine major glycoproteins demonstrated that the 75% of the GC content was conserved within most glycoproteins. Harrington et al. showed that the location of genes within the Ul regions of HSV and B virus were collinear; one gene rearrangement was described in an isolate which originated in a cynomolgus macaque. Homologues of HSV Us9 and Us10 genes were noted to be located upstream of the Us glycoprotein gene cluster in contrast to the downstream location of these genes in HSV Us region. This rearrangement was affirmed according to hybridization data and the proposed physical map of Harrington et al. Sequence analysis (unpublished) of the prototype strain (E2490) which originated from a rhesus macaque, however, illustrates that B virus DNA is colinear in these same regions with the HSV-1 genomic arrangement (L. Perelygina et al., 2000, unpublished data).

To date, sequences for only a few B virus genes have been submitted to GeneBank, i.e., homologues of gB, gD, gC, gG, gJ, and gI, largely covering the sequence of the Us region. Nonetheless, with a number of laboratories engaged in the sequencing of this virus, the majority of the genome sequence will be accomplished likely within a short time. Each of the glycoproteins for which sequence information is available, except gG, has about 50% identity with HSV, slightly higher for HSV-2 than HSV-1. B virus gG is a homologue of HSV-2 gG and is closer in size to gG-2 (699 kbp) than gG-1 (238 kbp). Glycoprotein sequences demonstrated that all cysteines are conserved as are the majority of glycosylation sites. This conservation suggests that B virus glycoproteins have similar secondary structure to that characterized in HSV. Sequence analyses from these laboratories also suggest that B virus and HSV types 1 and 2 probably evolved from a common ancestor. Using restriction length polymorphisms (RLPs), as a guide, several investigators have shown intrastrain variation among both human and non human primate derived isolates, the significance of which remains to be studied. Eberle et al. postulated the possible existence of B virus isolates, which vary with respect to pathogeneicity for non-macaque species, based on the existence of three distinct B virus genotypes found during phylogenetic analyses; however, this postulate must be examined in a suitable animal model. In zoonotic infections, unfortunately little is usually known about the species of most source animals, but where data are actually available many rhesus macaques have been identified targeting this species as the harbinger of a unique, highly pathogenic strain that can cause zoonoses. Published case summaries that implicate other macaque species and in one case a baboon, are difficult, if not impossible to confirm.

Synthesis of viral proteins

Approximately 23 major polypeptides have been identified by electrophoresis in denaturing polyacrylamide gels (Fig. 57.3), but over 50 different polypeptides have been identified by immunoblot analysis. Each has been assigned an infected cell polypeptide number as an initial reference point. The number may be an underestimate of the total produced, but it serves as a basis for comparison in ongoing studies. Molecular weight of these infected-cell polypeptides ranged from about 10 000–250 000 Daltons. Over 75% of the expected coding capacity of the viral DNA was accounted for by these infected cell polypeptides. At least nine bands from electrophoresed infected cell polypeptides containing viral glycoproteins have been thus far identified. Many of these glycoproteins have been cloned and sequenced by two groups. The proteins encoded were mapped to genes by the Us region which was largely colinear to the HSV glycoproteins gD, gI, gJ, and gG, as previously described. Sequence analysis of selected genes show that B virus is most closely related to herpesvirus papio 2 (HVP-2). Although there are protein homologues in herpesviruses of New World monkeys, very little, if any, cross-reactivity exists between B virus and the New World monkey herpesviiruses.

The kinetics of synthesis of the proteins and glycoproteins in infected cells in culture were found to have a course similar to that observed for HSV, although infectious virus was detectable slightly earlier, appearing 6 hours post-infection Both host cell DNA and protein synthesis appeared curtailed during the first 4 hours postinfection. As for glycoproteins, only glucosamine and some mannose were incorporated during the infection in vitro. B virus polypeptides/glycoproteins can be grouped into classes that differ in their relative rates of synthesis at different times throughout the virus replication cycle, as is characteristic of alpha herpesviruses.

Pathology and pathogenesis

During the course of B virus infection, some factors are observed not only in the natural host, but also in the experimentally infected host and the infected human as a result of zoonotic exposure. Those common factors will be discussed initially, then specific details for each of these host groups will be provided. First, there are various outcomes in infected hosts and evidence can be deduced from the literature that route of infection may play an important role. Specific details are lacking, but some observations can be made. The route of inoculation predicts differences in the time course of infection and spread through the central nervous system and visceral organs, e.g., spleen, adrenal, kidney, and in some cases even heart. Routes of infection are unique to each of the categories of hosts: natural, experimentally infected, and human zoonotic infections. For example, venereal transmission of the virus is common in macaque hosts, whereas intranasal virus can be experimentally delivered to a rabbit, or in the case of zoonotic exposure to a human by accidental aerosolization. However, these routes share one common feature, namely the involvement of mucosal membranes.

The cells that come into contact with the virus initially are another important factor to the permissiveness of the infection. For example, nasal mucosa has been found to be a less ideal site for virus replication than lung. However, nasal mucosa is not entirely resistant since increasing titers of virus can be isolated from these sites. Another important consideration in B virus pathogenesis is the dose of the virus initially introduced. The role of dose remains a challenging issue for study. Both dose and route of inoculation are important factors with respect to the onset of disease. For example, a far greater quantity of virus is required to infect rabbits by aerosolization than by an intradermal route of inoculation, although practically it remains unconfirmed whether these routes and doses parallel human versus non-human primate studies. Also, dose may be an important factor in contributing to associated morbidity and mortality. The commonality of each exposure route is generally a mucous membrane. Another common feature of natural, experimental, or zoonotic infection is that B virus can be found in the CNS shortly after the onset of acute infection. But where this virus goes and what it does differs widely in a natural infection versus an infection of a susceptible foreign host, the latter often succumbing to respiratory failure after neurologic deterioration.

The natural host

The macaque, the natural host of B virus, typically suffers little to no morbidity as a consequence of infection. Exceptions appear rarely and seem to involve specific accompanying factors, e.g., immunosuppression. Typically, once a macaque becomes infected following exposure of mucous membranes to virus, infection is relatively self-limiting. The virus may replicate at the site of inoculation and induce a localized erythema. There is also evidence of a limited focal infection of liver and kidney in some macaques. Virus travels via the peripheral nerves subserving the site of inoculation to associated dorsal route ganglia. Latent infection can then be established in the ganglia, with intermittent reactivation of the virus throughout the life of the macaque. In rare cases, viremia has been observed. Virus was also recovered from urine as well as multiple organs. Reactivation from latency has been observed in the natural host as judged by rising antibody titers as well as from recovery of virus by co-cultivation of sensory ganglia with cell monolayers.

During active replication of B virus in the natural host, isolation of virus can be readily accomplished from buccal, conjunctival, or genital mucosa swabs, predictable sites from which an alphaherpesvirus may be recovered during an active infection. The frequency of active infections within a seropositive group of macaques has been observed to be quite low, with relatively brief periods of excretion of virus from mucosal sites. Mucosal ulcers extend down to the papillary layer of the dermis. Two distinct zones have been described, namely a central area of necrosis and a surrounding zone of ballooning degeneration. Around the lesion, “normal” epithelium exists. An eosinophilic polymorphonuclear infiltration characterizes the histopathology of the lesion. Postmortem examination of monkey tissues from animals euthanatized at the time of active virus shedding shows histological evidence of perivascular cuffing of immune infiltrates in sections of spinal cord. Similar examinations of latently infected, healthy animals show no indication of virus from peripheral sites, but virus was recovered from sensory ganglia.

Experimental infections

Rabbits, mice, rats, guinea pigs and chickens have been experimental hosts of B virus as previously mentioned. Disease is not a uniform consequence following inoculation of B virus into mice and guinea pigs; however, several strains of B virus have increased virulence for the mouse. One strain, identified as E2490 was avirulent for white rats and chickens; nonetheless antibody developed after infection. Cotton rats infected by either intraperitoneal, subcutaneous, or intracerebral routes succumbed to infection with selected strains. Rats showed typical hind leg paralysis secondary to transverse meyelitis similar to symptoms in the rabbit. Reagan and colleagues selected, by serial passage human isolates of B virus, strains capable of infecting mice, hamster, and white chicks. With respect to experimental infections, a review of the literature suggests that the rabbit is perhaps the most useful small animal model since virus replicates in rabbits to high titers, making it a particularly good model for testing antiviral agents.

Using the rabbit, as well as the mouse model, investigators have shown that virus dose was important depending on the route of inoculation. Experimentally infected animals given low doses of intradermal virus developed only erythema that disappeared within a few days and was not associated with further apparent symptoms. In contrast, animals receiving a larger dose developed a necrotic lesion that was generally followed by CNS invasion. B virus subsequently appeared in the regional lymph nodes late after infection. These nodes drained the area of initial infection and with time, necrosis of the infected nodes occurred, as seen upon post mortem. In the CNS focal lesions were seen in pons, medulla, and spinal cord. Spread was most often facilitated by travel through the peripheral nerves, but in rare cases hematogenous route of spread in experimentally as well as inadvertently infected hosts has been described.

Cervical spinal cord and medulla oblongata were the primary sites for virus recovery post mortem. With time post infection, virus was found in olfactory regions of the brain, which may have been due to movement of the virus centripetally through the nerves innervating nasal mucosa. Perivascular cuffing and glial infiltration were characteristic histopathology findings upon examination of brain tissue. Hepatic congestion was accompanied by infiltration of polymorphonuclear and mononuclear cells seen in the periportal areas of the liver. Scattered necrotic foci can be found throughout the lobes of the liver. The presence of inclusions was seen mainly in the regions of inflammation, around pyknotic or karyorrhetic hepatocytes. When lesions were present on skin in the foreign host, the depth of the involved tissue was significantly thicker than that found on mucous membranes, explaining perhaps the reason B virus was recovered weeks or months later from these sites in foreign hosts.

Development of animal models for studies of B virus have been limited by the lack of antiviral drugs or a protective vaccine designed specifically to treat or prevent this infection since there is grave concern for individuals about actively working with this neurovirulent virus should an accident occur even when BL-4 laboratories are available and appropriate protocols are in place.

Human infection

Human infection with B virus generally occurs through an occupational exposure to a macaque shedding virus at a site which comes into contact with broken skin or mucosal membranes. Several cases where no monkey contact occurred in years suggested that virus could be reactivated. Review of all confirmed cases of B virus in humans can be summarized as follows.

The most striking characteristic of human B virus infection is the involvement of the patient’s CNS as a target of infection, specifically the upper spinal cord and lower brain.

These areas are the principal sites for virus replication as observed with clinical, laboratory, and post-mortem data, but initially the infected individual generally experiences a flu-like syndrome followed by numbness or parathesias around the site of inoculation. An ascending myelitis occurs during the final stages of the infection in humans, resulting ultimately in respiratory failure. Virus can be recovered at skin sites of inoculation for extended periods of time and viral DNA can be detected generally in cerebrospinal fluid by the time neurological symptoms are experienced. Antibodies can also be detected in the CSF. Generally, death is associated with respiratory complications. Cutaneous lesions, from which B virus can be isolated, sometimes develop late in infection. Edema and degeneration of motor neurons are prominent. Even with advancing disease Cowdry type A eosinophilic intranuclear inclusions can be found in only a few cases, and certainly not uniformly. Gliosis and astrocytosis are late histopathologic findings, thus, there can be evidence of myelitis, encephalomyelitis, or encephalitis, or combinations of each of these conditions.

Pathogenesis of B virus infection has been studied for each of the reported fatal cases and in some surviving cases. With fatal disease, generally, CNS lesions are localized within the upper cervical spinal cord, sometimes extending into the medulla and pons. In some cases hemorrhagic infarcts can be visualized in these areas, whereas in other cases damage appears minimal in spite of the fact that the patient generally succumbs after prolonged ventillatory support. In some cases, patients are alert, but paralyzed and in other cases patients remain in a comatose state which results in respiratory failure. Survivors have varying degrees of morbidity, seen, ranging from little-to-no sequelae to more severe, incapacitating sequelae. Some survivors experience slow progressive neurologic decline, whereas others report few if any effects long term. Several survivors have subsequently given birth to healthy babies with no ill effects for either the mother or infant. Monitoring of the vaginal canal for virus shedding in these individuals prior to delivery has been negative. In several reports, the ocular effects of B virus infection have been reported. Histopathological examination of the patient’s eye revealed a multifocal necrotizing retinitis associated with a vitritis, optic neuritis, and prominent panuveitis. A “herpes-like” virus was identified in the involved retina by electron microscopy in one case. Post mortem vitreous cultures taken from both eyes and retina have been positive for B virus. Thus, B virus can produce infection and destruction of retinal tissue similar to that of other herpesviruses. Ophthalmic zoster-like symptoms have been reported as well and in one particular case, reactivation of latent infection was speculated to have occurred.

To summarize human pathogenesis, the tissues and organs that become infected by B virus vary in some cases perhaps according to the route of infection. If skin is the primary site of infection, the virus usually, but not always replicates in the skin leading in some cases to localized erythema. Knowledge of the site of initial replication is useful for the development of guidelines for disease prevention and also for retrieval of a virus isolate that then allows unequivocal diagnosis. Subsequently, lymphangitis and lymph node involvement are observed. Viremia has not been proven to occur in humans, although with the application of more sensitive assays, e.g., polymerase chain reaction, further insights may be uncovered. With lymphatic involvement, the virus can spread abdominal viscera, where it has been isolated previously. Nevertheless, spread via neuronal routes is the fundamental route of transmission of the virus, as it is with HSV given the involvement of the spinal cord and CNS. Visceral organs, including heart, liver, spleen, lungs, kidneys, and adrenals demonstrate congestion and focal necrosis with variations in the extent of involvement from patient to patient. Recent human cases failed to demonstrate necrosis, but virus was isolated from adrenal, kidney, lung, and liver tissue collected at autopsy. In cases where B virus infection is suspected, medical personnel should follow published guidelines at the time of injury or observation of symptoms of possible infection.

Latency

A characteristic of all herpesviruses is the ability to become latent and reactivate when provoked with the proper stimulus. B virus is no exception. Reactivated infection has been described in both populations of macaques from the wild and captive established colonies. Unequivocal evidence of latent infection caused by B virus in macaques came with studies on frequency of recovery of B virus in monkey kidney cell culture systems. Wood and Shimada obtained six isolates from 650 pools of monkey kidneys, suggesting at least 1% of macaque kidneys contain latent virus that can be reactivated by culturing the cells. Virus was also isolated from rhesus tissues by Boulter and colleagues as well as by cocultivation from a variety of neuronal tissues including gasserian ganglia, trigeminal ganglia, dorsal route ganglia, and spinal cord. Latent virus was also isolated by cocultivation of tissues from experimentally infected rabbits, further supporting the rabbit as a potentially good animal model for B virus infections. Latency likely occurs in human infection as cutaneous recurrences have been documented and there are cases where an individual has not been in contact with macaques for years or even decades but antibodies exist at high levels.

As in HSV infections in humans, a prominent factor associated with reactivation of B virus in the macaque appears to be stress, particularly that associated with the capture and shipment of animals from the wild to captivity. Shedding of virus following reactivation also occurs with illness and during the breeding season of the natural host. No information is yet available on the state of the viral DNA during latency or on the molecular or biochemical events associated with the establishment and reactivation of latent virus.

Epidemiology

Animals

The majority of adult macaques and a very few younger animals in the wild have been reported to be seropositive for antibodies B virus. However, colonies of animals exist in the wild that have been found to be largely seronegative, but each of these colonies was established apart from original natural habitats to meet escalating needs of the scientific community and thus, the epidemiological pattern of virus infection was modified by human intervention. The high seroprevalence in macaques in the wild, the highly infectious nature within captive colonies, and low morbidity in this host confirmed the macaque as the natural host. More recent studies indicate that animals became infected at a higher incidence at the onset of puberty. The increased incidence appears to be associated with sexual transmission within the colony. Infants and juveniles have been reported to demonstrate a very low incidence of infection as judged by the low prevalence of B virus antibodies. Since antibody levels may reflect presence of maternal antibody in animals in contact with dams, it is of importance that both age groups are virus positive, suggesting transmission other than sexual activity occurs.

No particular species of macaque appears to be excluded as a natural host for B virus infection, although there is minimal data available from certain species and absent in the case of others. Although presence of antibodies has been confirmed in the majority of the different species of macaques, there has been speculation that virus isolated from certain species is less neurovirulent or less neurotropic than virus shed by rhesus macaques. Differences in the restriction endonuclease profiles of the different isolates from different macaque species have been reported, but the lack of available data on the types of macaques involved with each of the documented human cases has not permitted rigorous evaluation of this hypothesis.

Virus shedding during either primary or recurrent infections has been noted to occur at unpredictable frequency with widely variable duration. Analysis of available data indicates that macaques shed virus for a longer duration during primary infection, and for short periods, even hours following reactivation. Levels of shed virus, as measured from mucosal swabs range from 102–103 pfu/ml in one diagnostic laboratory.

Humans

B virus is an infection that humans rarely contract, but when they do, nearly 80% of untreated cases result in fatality. Epidemiological analysis indicates B virus is usually acquired via zoonotic transmission from either a macaque or infected cells or tissues from the animal. There is, however, one documented case of transmission from human-to-human as previously described, supporting the assumption that B virus can be transmitted similarly to HSV-1 or HSV-2, through mucosal contact with virus which is sometimes present in secretions or wound sites. A recent fatal case which resulted from exposure of ocular membranes to virus from a monkey in the process of being transported refocused attention on an earlier report implicating this type of transmission in the epidemiological analysis of zoonotic transmission of the virus. Current analyses of cases suggest categorization of risk levels with regard to the severity of injury is not useful. The low incidence of B virus infection in humans makes it difficult to reach statistical conclusions, but analysis of cases occuring during the last decade support the fact that first aid of injured or contaminated sites plays a major role in infection control. Only minimal disruption of the protective skin layer or instillation directly to a mucosal membrane can result in initiation of infection when the site is exposed to viable virus. The level of virus needed to initiate an infection in humans remains unknown. Where data are available, rhesus macaques were most frequently implicated as the source of infectious virus in reported human cases, but alone this is insufficient to conclude that the rhesus is uniquely important in the establishment of zoonotic infections. Other species of macaques and even a baboon have been linked to fatal zoonotic infections.

The incidence of zoonotic infections has been correlated retrospectively with periods of increased usage of macaques particularly in biomedical research. Evaluation of past cases underscores that transmission of the virus is often associated with no more than a superficial scratch or puncture, suggesting that once virus gains entry into a host, the ability to initiate disease is perhaps dose independent, at least in some cases. However, this point remains unsubstantiated. Dose and route of entry are topics that require further study to clarify importance in zoonotic infection. Likewise, incidence and prevalence of zoonotic infections must be estimated cautiously since little data regarding the virus source is available from clinically recognized cases.

Host immune responses

Antibodies specific for B virus have been studied in both the natural and the foreign hosts by a wide variety of methods, including serum neutralization with or without complement, competitive RIA, multiple types of ELISA including competition ELISA, and western blot. Limited serial observations have been available from both the natural or foreign host, but comparison of available data have been useful in that relatively consistent responses are induced in both hosts. The time course over which antibodies develop has been measured in wild macaques, captive colony populations, individually imported animals, experimentally infected macaques, zoonotically infected humans, and even in vaccine trial recipients. The ELISA methodologies provide a rapid diagnostic tool with increased sensitivities of detection, and enhanced specificity when competition protocols are utilized. The antibodies which develop in response to herpes B virus infection in both humans and non-human primates are capable of neutralizing HSV-1 and HSV-2, as well as non human primate alpha herpesviruses. The HSV antibodies are not able to neutralize B virus, indicating the presence of virus specific antigens unique to B virus. Sequence data have been useful in confirming the existence of virus specific epitopes.

The humoral immune responses which develop after a B virus infection either in the susceptible host, either natural or foreign, had characteristic patterns of viral antigen recognition throughout the course of infection. The glycoproteins induced antibodies early in the course of infection. Antibodies began to appear within 7–10 days after the infection and consisted of IgM. Within 14–21 days after the onset of acute infection, IgG antibodies were present. In rare cases, the infected host remained persistently antibody negative in spite of virus isolation. The pattern of the immune response was altered in the cases of humans who have had a previous infection with HSV-1 or HSV-2, since viral antigens that are shared among the three viruses induce an anamnestic response toward shared protein or glycoprotein sequences. Neutralizing antibodies develop in both the natural and foreign host, but at significantly lower levels than the foreign host. The nature and specificity of the humoral responses make it possible to design enhanced serological testing strategies to rapidly identify detectable antibodies and will provide the basis for future diagnostic strategies.

Clinical manifestations of disease

Observation of the clinical pattern of disease is important for rapid diagnosis of B virus infection in both macaques and humans. In the natural host, recognition of early infection allows removal of infected monkeys from captive colonies that are being established as B virus-free. In B virus-free colonies, it is important to remove seropositive animals and isolate animals with equivocal results to prevent infection of other colony members, or in seropositive colonies to minimize risk to humans who have to handle them. Macaques are not treated with antivirals since the prevalence of infection is generally cost prohibitive. In the case of humans, early recognition of disease facilitates treatment with antivirals, principally nucleoside analogues, a course which appears to significantly lower the morbidity and mortality. Notably, immunosuppression, e.g., administration of corticosteroids, is often associated with reactivated mild disease in the natural host, whereas other agents appear to be capable of facilitating systemic B virus dissemination, culminating in death.

Humans exposed to herpes B virus demonstrate clinically variable signs of infection. Most often, illness after exposure to viable virus is apparent within days to weeks, but in some cases there appears to be a delay in development of acute disease. The reasons for this delay are unknown and, though rare, delays may even range from months to years, making diagnosis difficult. Once symptoms appear, the clinical progression is associated with relatively consistent symptoms, including flu-like illness, lymphadenitis, fever, headache, vomiting, myalgia, cramping, meningeal irritation, stiff neck, limb paresthesias, urinary retention with an ascending paralysis culminating in inability of the patient to maintain respiration, requiring ventillatory support. Cranial nerve signs, e.g., nystagmus and diplopia are also common to most published cases. Sinusitis and conjunctivitis have been observed in some. The array of symptoms may be related to the dose of virus with which the individual was infected or the route of inoculation. Summary descriptions of human cases can be found in two comprehensive reviews.

A summary of reported cases indicates that the highest percentage of deaths post infection occur within weeks postonset. In some cases however life was prolonged artificially for months or years. Incubation times from identifiable exposures to onset of clinical symptoms ranges from days to years, but the majority of cases occur within days to months. Virus has been recovered from throat, buccal, and conjunctival sites, as well as from lesions, vesicles, or injury sites as late as weeks to months post infection. The majority of clinical cases are associated with bites (50%), with fomites (8%) saliva (<5%), and aerosols described as other modes of exposure (10%).

Diagnosis

Non-human primates

B virus infection in macaques is identified by either virus isolation or the presence of specific antibodies or both. The neutralization assay dominated as a diagnostic tool in macaques and humans for many decades. The time required for the results of this test was often a drawback. The dot-blot, RIA, ELISA, and western blots were subsequently developed. Three of these techniques rely on the use of monoclonal antibodies. Each of these tests can be accomplished in less than a day, and are available through commercial laboratories as well as through a national resource laboratory subsidized through NIH’s National Center for Research Resources. All of these assays utilize B virus infected cells for antibody detection, making them more effective than other types of assays which rely on HSV-1. This is a particularly important point with respect to diagnostic tools utilized to recognize early laboratory signs of infection for the establishment of B virus-free colonies. Currently, there are no diagnostic serologic tools to identify infected macaques that lack detectable antibodies; however, there are some promising assays being developed for diagnosis of HSV-2 infections in humans that may be adapted for identification of B virus infection in macaques. When selecting an assay for detection of antibodies, the sensitivity and specificity of the test for a specific species of macaque should be known and considered in the final evaluation of the results. Tests dependent on monoclonal antibodies or recombinant reagents should have defined sensitivity and specificity for each macaque species to be tested. Finally, evaluation of a macaque is optimal when analysis is performed on multiple samples collected at different times, especially in cases when the antibody titer is low (<1:50). A constellation of different tests at numerous time points may be necessary in some cases to correctly determine the status of an animal with low antibody titers, particularly when such an animal is housed in a B virus-free colony.

Virus isolation is the gold standard for diagnosis of infected macaques. Unfortunately, virus isolation is not a particularly sensitive diagnostic tool, with the possibility of many false negatives. Nonetheless, standard cell culture for virus isolation is still a valuable tool for the colony manager and for the veterinarian. Virus positive cultures can be easily recognized with the unique cytopathic effect produced by B virus, but unequivocal confirmation of the identification requires either electrophoretic analysis of infected cell polypeptides or restriction endonuclease digested DNA. More recently, several PCR reactions have been described which can be used to verify the identity of the virus; however, this diagnostic tool is costly for colony management. Nonetheless, when a possible zoonotic infection must be confirmed, PCR may be beneficial for identification of B virus in macaques.

Other species of monkeys become infected infrequently with B virus. These are usually animals that have been co-housed or housed in close proximity to B virus infected macaques at some time. Since many, if not all non human primates harbor indigenous alpha herpesviruses, the important diagnostic point is to differentiate specific antibodies from cross-reactive ones. Euthanasia is generally advised in the case of a B virus infection in a non-macaque monkey since it is likely that the animal will succumb and, in the meantime, would pose a great risk to anyone attempting to treat the infection. B virus has been identified in the patas monkey, colobus monkey, and Debrazza and Thompson et al. (in press). In each case, there was a major concern for the people responsible for care of the animal, particularly since these animals often have severe morbidity and are shedding virus. Currently, the most effective assay for diagnosis of B virus in a non macaque monkey would be a competition ELISA to facilitate discrimination between specific and cross-reactive antibodies similar to the challenge faced when diagnosing infection in humans.

Humans

The evaluation of clinical symptoms associated with an antibody or virus positive case is the gold standard for diagnosis of B virus infection in an exposed individual. Both serological and virological techniques are available for diagnosis of B virus infected humans. The CDC has published specified guidelines for recognition and treatment of such infections. In the case of a suspected infection, several emergency resources are available. Contact with the CDC or the laboratories recommended in the CDC guidelines can expedite laboratory support for the clinician suspecting an infection. Generally, a rise in B virus specific antibodies over several days during acute infection can be used to the etiologic agent. However, in other cases, data are equivocal and decisions with regard to the patient must be based on a complex decision table collectively using all diagnostic tools, including clinical symptoms. Virus isolation is again the gold standard for diagnosis, however virus isolation is frequently not possible even under the best of circumstances. Serological diagnosis of B virus in humans is a complex task when an individual with a suspect infection has detectable antibodies as a result of a previous HSV-1 or HSV-2 infection. As discussed in a previous section, significant cross-reactivity exists among these viruses. In the absence of these cross-reactive antibodies, diagnosis is rapid and straightforward, with confirmation using the neutralization assay and/or western blot. This was not the case prior to the development of rapid diagnostic competitive ELISAs and RIAs. The diagnostic tests for humans are performed currently by only a few facilities that have been licensed and have access to BL-4 containment laboratories for the preparation of B virus antigen.

Virus identification can be accomplished by isolation using conventional cell culture, and in clinical emergencies with PCR. The identity of isolates should be confirmed by electrophoretic analysis of infected cell polypeptides or restriction endonuclease digested DNA. The application of PCR is most helpful in the symptomatic patient if virus cannot be recovered. PCR is also a useful tool for monitoring the efficacy of antiviral interventions.

Control of B virus infection

Multiple levels of prevention can be used to prevent B virus infection in both humans and non-human primates, ranging from attempts to eliminate virus to designing methods to work safely in environments where there is increased risk for contracting this agent. The CDC has published detailed guidelines for maximizing protection for individuals working with macaque monkeys. Further, the NIH’s National Center for Research Resources has funded the development of B virus-free colonies for NIH-funded research involving these animals in attempt to ultimately eliminate this virus from colonies used for biomedical research. Nonetheless, B virus infected monkeys are plentiful and require attentive handling adhering to strict guidelines, including barrier precautions.

When B virus is present, it can be inactivated with either heat or formaldehyde. Other inactivators include detergents and bleach. Individuals who work in a decontaminated area should still be alert to injury prevention. Minimizing fomites, however, decreases worker risk and reduces virus spread among animals. One B virus infection in a human was acquired from a cage after sustaining a scratch, underscoring that surface decontamination is important in infection control.

As early as the 1930s, attempts were made to identify an effective vaccine for protection of individuals who could be exposed to this virus while working with macaques or their cells or tissues. Limited vaccine trials were performed in human volunteers and although short-term antibody was induce, it was observed to wane quickly and the vaccine was not pursued further at that time. Recently, a recombinant vaccine was tested and found to induce antibodies in macaques, but the duration of antibodies and protection remain to be studied.

Antiviral therapy has been recognized as an effective prevention of infection progression in humans and animal trials as well, when administered sufficiently early after exposure. Acyclovir and the related family of nucleoside analogues were noted to be effective when given in high doses, e.g., acyclovir at 10–15 mg/kg three times daily for 14–21 days. Efficacy of therapy in cases of infection in humans has been monitored by inhibition of peripheral virus shedding in some cases and by reduction in CSF antibodies or viral DNA load in others. Ganciclovir has a greater efficacy in vitro and thus was used in all proven cases since 1989 with success. Interestingly, prior to 1987, in at least five retrospectively recognized cases, individuals fared well in the absence of antiviral therapy, but overall, the use of acyclovir and ganciclovir remains the recommended therapy by CDC. Generally, antiviral therapy is reserved for human with a clinically apparent infection, however it is also used by an increasing number of facilities for post-injury prophylaxis or after laboratory results indicate an animal may have been actively infected around the time of the exposure. Postinjury prophylaxis has been performed with famciclovir or valcyclovir, as well, both in that have demonstrated efficacy in vitro. Recommendations and guidelines have been published by the CDC, as discussed previously and can be readily accessed. Only a handful of physicians have had experience in the treatment of B virus zoonosis and their participation and expertise were important in the development of the CDC guidelines.

Finally, with respect to prevention, the value of wound cleansing following a potential exposure due to a bite, scratch, splash, or other suspicious injuries is very mandatory. Guidelines for wound cleaning are described in detail in the CDC Guidelines. Every institution working with macaques should have an injury protocol with immediate availability of first aid, a secondary care plan, and last but not least an infectious disease specialist who is a member of the institution’s prevention and care response team.

Conclusions

B virus is usually a rap054 advancing, devastating disease which can be interrupted with effective use of antiviral therapies if deployed sufficiently soon after infection. The guidelines for treatment and prevention are widely published and can be rapidly accessed either through CDC or the diagnostic resource using the world wide web address www.gsu.edu/bvirus. Diagnostic techniques are rapidly improving to support clinical diagnosis and information regarding sample collection and evaluation is available at any time to clinical care centers in case of emergencies.

With the newer diagnostic techniques, sensitivity of detection is imp055 and the barriers posed by the high degree of cross-reactivity among this family of viruses are rapidly being diminished.

Because of the risk of human disease, p056 methods must be followed in the workplace. Proper attention to the details of housing, management, handling of macaque monkeys, and organized exposure response measures using the CDC guidelines can minimize B virus zoonotic infections. Rapid identification of infection is essential for early inititation of antiviral drug therapy which can prevent further mortality associated with this very interesting alphaherpesvirus.

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