B-Virus (Cercopithecine herpesvirus 1) Infection in Humans and Macaques: Potential for Zoonotic Disease – Volume 9, Number 2—February 2003 – Emerging Infectious Disease

B-Virus (Cercopithecine herpesvirus 1) Infection in Humans and Macaques: Potential for Zoonotic Disease - Volume 9, Number 2—February 2003 - Emerging Infectious Disease

“So far we have not found any indication of monkeys being infected with rabies. RESERVOIR AND INCIDENCE Sheep and goats worldwide. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Most macaques carry B virus without overt signs of disease. Its remains were allegedly sent to the Veterinary School at Mississippi State University. Vito G. By their very nature, these animals are wild and potentially dangerous and, as such, do not adjust well to a captive environment.

In this setting, human contact directly with macaques or with their tissues and fluids sometimes occurs. Acute stomatitis in pet monkeys can suggest HHV-1 infection, among other diseases, and systemic treatment with acyclovir may be appropriate. Neuropathological evaluation revealed that all four SIV-infected monkeys exhibited numerous perivascular and parenchymal infiltrating T cells. Fortunately, most pet monkeys in this country are new world species and are bred in this country. Also, as they age, their behavior can become unpredictable and sometimes violent, depending on the circumstances in which they’re kept. However, the death rate for B-virus infection before the availability of antiviral therapy is >70%. Neurologic sequelae are common in survivors.

RESERVOIR AND INCIDENCE Animals: Nine reported outbreaks in captive NHP’s, primarily rhesus and cynomolgus. SIV infection of rhesus monkeys provides an excellent model of HIV infection and AIDS, including the CNS sequelae (7–9). Two research groups obtained samples from patient W.B.: Gay and Holden and Sabin and Wright (1,2). An applicant shall have the burden of proving that any wild animals subject to this chapter are or will be imported, transferred, sold, purchased or possessed in compliance with this chapter and regulations. The high specificity of many biopharmaceuticals, and in particular those with monoclonal antibodies, means that most preclinical studies use nonhuman primates due to target-specific cross reactivity, relevant pharmacology, similar immune systems, and similar pharmacokinetics (Chapman et al. And why do some vaccines have live pathogens but others have killed pathogens? Simian B Virus Infection is caused by a type of herpesvirus.

Figure. SIV invades the brain soon after the experimental intravenous infection (18, 19, 20, 21). The organisms most often encountered in the mouths of rhesus monkeys are the Neisseria species, alpha hemolytic streptococci, and Haemophilus parainfluenza. The imported prairie dogs were mingled with domestic prairie dogs available for sale, transmitting the monkeypox virus to them and on to humans. The viral genome is G+C rich (75% G+C), the highest of any known herpesvirus (4). The B-virus genome is only partially sequenced, but thus far, is colinear with that of HSV (5). Case fatality rate 10-15%.

Animals were kept in a containment facility and handled for experiments after intramuscular administration of anesthesia with ketamine. For HSV, 11 glycoproteins are known (gB–gM), and another is predicted (gN). Of these, nine have been identified in B virus (5). Consequently, other NHP sources, particularly in China and Southeast Asia, are being used. Even a scratch will put the pathogen in your blood stream, and unholy reanimation soon follows. Such protocols can have life-or-death implications, as the herpes B virus has proved fatal in approximately 80 percent of known cases. Lanes 1 and 2 represent amplification products of HHV-1 strain Wal (229 bp) and HHV-2 strain D316 (241 bp), respectively (Figure).

Electrophysiological studies were accomplished during anesthesia (ketamine, 20 mg/kg, i.m.), between 37 and 52 weeks after infection with SIV. The virus establishes latency in the nerve ganglia. Breed- and species-specific rescue groups exist in most states and in many cities and metropolitan areas. Periodic reactivation from latency delivers the virus to mucosal epithelial cells, where it replicates; infectious virus is released from the mucosal epithelium. A heavy viral load in the ganglia may increase the frequency of reactivation and shedding (8). Aerosol transmission has been proven experimentally. Virus recovery from the CSF was performed by a coculture assay.

B-virus infection has been reported most commonly in the rhesus and cynomolgus macaque (M. facicularis), two species used extensively in biomedical research. Facilities therefore either maintained SRV-positive animals or reinfected colonies up until the late 1990s, when virus isolation techniques, in conjunction with serologic screening and SRV polymerase chain reaction (PCR) techniques, helped to establish SRV-free colonies (Guzman et al. Will One Doctor’s Radical New Vaccine End the AIDS Epidemic? As many as 90 percent of all macaque monkeys are infected with herpes B virus, which harmless to monkeys but often fatal in humans. In New World monkeys, however, HHV-1 seems to act more like a CeHV-1–type ”killer virus” (5,15). A frequency of 1/sec was used to generate AEPs.

cyclopis) macaque (12). Sequence comparisons and restriction fragment length polymorphism analysis of viral genomes have demonstrated strain differences between B-virus isolates from different macaque species (13). Research suggests that B virus from rhesus macaques may be more pathogenic for humans than B virus from other macaque species (13). Where the species of macaque is noted, cases of human B-virus infection have all been associated with direct or indirect exposure specifically to rhesus macaques (14–19). TRANSMISSION: Aerosols or vectors. Plasma and CSF concentrations of monocyte chemoattractant protein-1 (MCP-1) were determined by ELISA (R&D Systems Inc., Minneapolis, Minnesota, USA). Infection is usually acquired at sexual maturity (2–4 years of age for rhesus macaques).

As seen in humans with HSV, B-virus seropositivity increases with population age; seropositivity rates of 80% to 100% occur among most adult captive macaque populations (10,20,21). 1985). I really hope that this drug will get commercialized if all trials go well and that the price won’t be out of the reach of regular people. In general, macaques remain asymptomatic, and identification of oral herpetic lesions is sufficient grounds for euthanasia of the affected animal. For more information, view the biosafety manual prepared by the Centers for Disease Control and Prevention and the National Institutes of Health at http://www.orcbs.msu.edu/biological/BMBL/BMBL-1.htm. Reinforcer efficacy was probed at the end of each week using a progressive-ratio schedule, in which the number of responses required to obtain a food pellet was increased progressively throughout the session. Relatively few studies have surveyed macaques for B-virus shedding, and detection of B virus by culture is rare.

Most cases of B-virus detection in asymptomatic macaques by culture or PCR are associated with breeding season stress (9,10), immunosuppression (25), or primary infection (10,11). The true frequency of B-virus shedding in macaque populations is not known but is likely to be low. Most cases of human B-virus infection have been associated with apparently healthy macaques (i.e., no obvious herpetic lesions), which indicates asymptomatic shedding of the virus. HERPES B Disease Overview: Institutional Animal Care and Use Committee, University of California, Santa Barbara. Electrophysiological analysis of brainstem auditory–evoked potentials (BSAEPs) was performed on ketamine (20 mg/kg) anesthetized animals as described previously (10, 26). Most cases of human B-virus infection have involved direct contact with macaques, such as a bite, scratch, or mucosal contact with body fluid or tissue (12,14–16,19,27,28). Indirect contact, such as injury from a contaminated fomite (e.g., needle puncture or cage scratch), has also resulted in human infection.

STLV infection is usually asymptomatic, with only a small number of infected animals developing T cell lymphoma or lymphoproliferative disease (Lerche and Osborn 2003). Human B-virus disease generally occurs within 1 month of exposure (21), commonly with an incubation period of a few days to a week. The development and progression of disease depend on the site of exposure and the amount of virus inoculated. Anais. No significant inter-test variability was observed. Other variable symptoms include lymphadenitis and lymphangitis, nausea and vomiting, abdominal pain, and hiccups (12,14). Neurologic signs develop when the virus spreads to the central nervous system and vary with the part of the brain or spinal cord affected.

Hyperesthesias, ataxia, diplopia, agitation, and ascending flaccid paralysis have been described after virus spread to the brain (12,14–19). Virus spread to the central nervous system is an ominous sign; even with antiviral therapy and supportive care, most patients die, and those who survive often have serious neurologic sequelae. A new Powassan-like virus has recently been isolated from deer ticks. The ANOVA used the between factor of infection and the within factor of treatment (three levels: saline 1, PMPA, and saline 2). A carefully controlled study of B-virus antibodies in persons with macaque contact and controls without contact showed no evidence of asymptomatic human infection or a carrier state for B virus (29). Although HSV antibodies can neutralize the virus in vitro, antibody titers to HSV are not protective in human cases of B-virus exposure or infection (21,29) and can confound diagnostic testing because of cross-reactivity. Animals exposed to measles have lifelong immunity, so quarantine and vaccination can be effective in the prevention of disease (Willy et al.

B-Virus (Cercopithecine herpesvirus 1) Infection in Humans and Macaques: Potential for Zoonotic Disease - Volume 9, Number 2—February 2003 - Emerging Infectious Disease
With the discovery of simian immunodeficiency virus and its identification as a model for HIV infection, the number of macaques used in research has increased, as has the number of human B-virus cases. Guidelines for reducing and controlling exposure were first published in 1987 (26) by a group of veterinarians, physicians, and research scientists called the B Virus Working Group. Guidelines were again published in 1995 (21) by a new B Virus Working Group to include new information and provide protocols for handling exposures. Note that waves P1–P4 and P1–P5 show significant delays in the SIV-infected monkeys. New guidelines by another B Virus Working Group have recently been published (30). The 2002 B Virus Working Group guidelines address issues to be considered in cases of possible exposure to or infection with the virus (30) and reflect consensus of opinion at the time the guidelines were written. In cases of exposure, an established and frequently updated protocol should be used based on these guidelines and on current literature regarding human cases of B-virus infection.

Additional information and contacts are available from: URL: http://www.cdc.gov/niosh/hid5.html, http://www.haz-map.com/Macaque.htm. diseases. PMPA therapy itself had no effect on the evoked potentials of uninfected monkeys (Figure , top). Bite wounds, scratches, or puncture wounds of nonmucosal surfaces should be cleansed with soap or detergent for at least 15 min (30). The time spent mechanically cleansing the area is more important than the type of cleansing solution used. 2004). Immediate cleansing or rinsing can inactivate and wash away virus present in the exposure site.

After immediately cleansing the wound or exposure area, the person should seek medical attention, specifically from a physician identified in the facility’s protocol as someone familiar with treating these B-virus exposure cases. A physician with a patient who has potentially been exposed to B virus faces a conundrum. ∗, P < 0.05. However, few cases of potential exposure lead to infection. Prophylactic treatment is unnecessary in most cases of potential exposure because treatment can confound diagnostic testing by interfering with the humoral immune response (21). However, the 2002 B Virus Working Group viewed prophylactic treatment more favorably in light of the efficacy of postexposure prophylaxis for nosocomial HIV exposure and the availability of new antiherpes drugs, such as valacyclovir, that achieve higher serum levels with a more reasonable dosing schedule (30). Although severity of injury may prompt use of antiviral therapy, the amount of inoculated virus determines if infection is likely to occur. Such disaster declarations usually occur when the vector-borne disease has the potential to infect large numbers of people, when a large population is at risk and when the area requiring treatment is extensive. Effects of PMPA and SIV infection on movement and temperature. Inadequate cleansing of the wound or exposed area in a timely manner could warrant prophylactic antiviral therapy. Other indications for immediate initiation of antiviral treatment include the identification of herpetic lesions in the source animal, injuries involving the head or neck, and mucosal exposure to macaque fluid. 2007; O'Sullivan et al. In addition to working closely with a physician trained to handle cases of B-virus exposure and infection, taking samples from the exposed person and the source animal is important for virus culture and serologic testing. A list of recommended swabs for virus culture and serum samples is available from: URL: http://www.gsu.edu/~wwwvir/index.html. Early suspicion and rapid diagnosis of B-virus infection are critical to the control of human infection. Performance in the behavioral tasks was evaluated for the period surrounding electrophysiological recording (Table 1). Despite the inherent risk for exposure, direct culture of B virus has been the standard for diagnosis of infection. Culture of B virus requires a special containment facility since the virus is a biosafety level 4 pathogen (31). Serologic methods for the detection of B-virus infection have also involved propagation of the virus in tissue culture to produce antigen. However, the substitution of related antigens appears to work well for serologic tests. While polymerase chain reaction (PCR) has been developed to identify a number of viral agents, such tests have not yet been validated for routine rapid identification in the clinical setting. Although PMPA has not been directly studied, a closely related drug, 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) is poorly accessible to the CNS after peripheral administration (29). More recently, PCR methods have allowed direct demonstration of B-virus infection without the risk of working with virus cultures (9,34,35). PCR methods have been hampered by the close genetic relationship between primate alphaherpesviruses; many require post-PCR techniques to definitively differentiate between HSV and B virus. 1997). Samples to be tested by PCR may contain B virus and must be handled accordingly (31). The cases of human B-virus infection that have been described have all occurred in relation to contact with macaques in a biomedical research setting. However, this setting is not the only one in which humans have contact with macaques. The last SIV-infected monkey (monkey 193) was sacrificed at 71 weeks after infection due to a progressive gingivitis. recently culled all B-virus–positive macaques from its facility (36). No cases of human infection have been documented despite contact between macaques and humans driving through the park, but the risk perceived by this situation warranted the action. B virus is also prevalent in free-ranging macaques native to Southeast Asia (12,37). A recent survey of workers at a Balinese Hindu temple that is a refuge for free-ranging macaques and a tourist attraction showed that contact between humans and macaques sufficient to transmit B virus commonly occurred. Recently, more cases are being reported from states in the mid-Atlantic (West Virginia, Virginia and North Carolina) and southeastern (Alabama and Mississippi) regions of the country. Histopathology in the CNS of PMPA-treated, SIV-infected monkeys. However, in cases of encephalitis, B virus may not be considered. In other situations, particularly when potentially seropositive macaques have been domesticated as pets, opportunities for exposure to B virus are frequent. HAV can infect a variety of Old and New World NHPs including the great apes, cynomolgus, rhesus, and stump-tailed macaques, owl monkeys (Aotus sp.), marmosets, and baboons (Balayan 1992). This study also found that children were three times more likely than adults to be bitten by pet macaques. Although the number of macaques kept as pets is probably small, the risk of B-virus infection is increased because of the lack of precautions and the extent of contact between monkey and owner. The risk of B-virus infection is low, but the risk for death is high. One advantage of the Cambridge Neuropsychological Test Automated Battery is that data collected in monkeys can be directly compared with data collected in human patients. The timing and local nature of B-virus reactivation and shedding make detecting infection in an animal difficult. Therefore, serologic methods are used to screen and monitor animals for consideration as pathogen-free. Numerous negative serologic results are necessary to determine a macaque’s B-virus status. Although specific pathogen-free status reduces the likelihood of infection, this status does not eliminate the risk for infection entirely. Approximately one-third of all people with clinical encephalitis caused by EEE will die from the disease and of those who recover, many will suffer permanent brain damage with many of those requiring permanent institutional care. Interestingly, the CSF of monkey 299 contained almost one log less of virus than did the CSF of monkey 294, despite the finding of quantifiable SIV in the brain of monkey 299 but not in monkey 294. While antiviral therapy has substantially improved the survival rate for human B-virus infection, fatal cases still occur (19,28). The ability of the virus to modulate and evade the immune response has stymied vaccine development for most herpesvirus infections. 1985). Given the lack of an effective vaccine for HSV after years of research effort and clinical trials, development of a B-virus vaccine presents a challenge. A formalin-inactivated B-virus vaccine was developed and tested in the 1960s (39). Although this vaccine did induce an antibody response, antibody titers were low, and frequent boosters (every 3 months) were required (39). This abnormality indicates a common pattern in which virus infection leads to a functional pathophysiology of the brainstem. A DNA vaccine against B virus has also recently been described (41). Glycoprotein B of B virus delivered in a plasmid vector induced a humoral response in both mice and rhesus macaques. Although no challenge experiments were performed in monkeys, an anamnestic-like response upon boosting was noted. While the ability of a B-virus antibody response to protect from infection is not known, studies of HSV suggest that an antibody response alone is not protective. When health officials maintain surveillance for EEE virus activity, this movement out of the swamp can be detected, and if the level of activity is sufficiently high, can recommend and undertake measures to reduce the risk to humans. After cessation of PMPA treatment, peripheral viral load recovered quickly, whereas the BSAEP latency delays reappeared 2 months after the end of treatment. The potential for fatal human infection with B virus is a constant concern because frequent exposures occur to humans in the course of caring for and using macaques in a research setting. Personal protective equipment and safe handling procedures have limited the incidence of human disease. alone were associated with acute intestinal disease in NHPs (Kalashnikova et al. A clear understanding of the real risk for B-virus shedding in its natural host will help identify opportunities to prevent or limit zoonotic B-virus disease. Dr. Huff is a postdoctoral fellow at the University of California, Davis. Hence, these findings would strongly encourage the analysis of AEPs in HIV+ and AIDS patients. Barry at the Center for Comparative Medicine. Dr. Huff studies infectious diseases in the rhesus macaque model system. Dr. In addition to Cx. MCP-1 is a potent chemoattractant not only for monocytes but also for activated T cells and is capable of directing the migration of monocytes, as well as some lymphocytes, across a model of the BBB (38). Barry’s primary research addresses the mechanisms of rhesus cytomegalovirus persistence and pathogenesis. He is also working to improve B-virus diagnostics and understand B-virus pathogenesis in the CNPRC macaque colony. flexneri and Campylobacter spp. Department of Health and Human Services, PHS, Centers for Disease Control and Prevention, National Institutes of Health. Biosafety in microbiological and biomedical laboratories. 4th ed. This work was supported by National Institutes of Health Grants P50-MH47680 to F.E.B. Government Printing Office; 1999.

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