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B virus

The B virus, also known as Herpesvirus simiae or cercopithecine herpesvirus 1, is an alphaherpesvirus that naturally infects macaque monkeys, serving as their reservoir host, and can cause severe, often fatal zoonotic infections in humans upon direct contact with infected animals or their tissues.^[1] Endemic to species such as rhesus, cynomolgus, and pig-tailed macaques, the virus is highly prevalent, with over 70% of adult macaques carrying it asymptomatically or experiencing mild oral lesions similar to herpes simplex virus in humans.^[1] In monkeys, infection typically occurs early in life and persists lifelong, shedding intermittently through saliva, genital secretions, or urine, particularly during stress or immunosuppression.^[2] Human infections with B virus are extremely rare, with only about 50 documented cases worldwide since the first reported in 1932, primarily among laboratory workers, veterinarians, or individuals handling pet macaques, though a single instance of human-to-human transmission has been recorded via indirect contact with material from an infected wound.^[1] Transmission to humans occurs through bites, scratches, or exposure of mucous membranes and broken skin to infected monkey fluids or tissues, with no evidence of airborne or casual contact spread.^[2] The incubation period ranges from 3 to 30 days, often manifesting initially as flu-like symptoms including fever, chills, headache, and fatigue, followed by vesicular lesions at the exposure site that may progress to severe neurological complications such as encephalitis, myelitis, or paralysis if the virus reaches the central nervous system.^[3] Untreated, B virus infection has a mortality rate exceeding 70%, with survivors frequently suffering permanent neurological deficits; however, prompt antiviral treatment with drugs like acyclovir or valacyclovir can improve outcomes if initiated early.^[1] Prevention relies on avoiding direct contact with macaques, especially in research or exotic pet settings, and implementing strict biosafety protocols including immediate wound decontamination with soap, detergent, and water following potential exposure.^[2] No vaccine is currently available, and diagnosis requires specialized testing due to serological cross-reactivity with human herpesviruses, typically performed at reference laboratories like the National B Virus Resource Center.^[4] Ongoing surveillance highlights the virus's potential as an emerging threat in regions with growing human-macaque interactions, such as in wildlife tourism areas; for example, Hong Kong reported its first human case in 2024, involving a man injured by wild monkeys.^[5]^[6]

History and discovery

Initial identification

The B virus was first recognized in 1932 following a fatal incident involving William B. Brebner, a 29-year-old physician and researcher at the New York City Department of Health laboratories. On October 22, 1932, Brebner was bitten on the dorsum of his left ring and little fingers by an apparently healthy rhesus macaque (Macaca mulatta) during poliomyelitis experiments. The wound initially appeared minor and healed without immediate concern, but by October 25, local pain, redness, and swelling developed, progressing to vesicles, lymphangitis, and regional lymphadenopathy. Systemic symptoms emerged around November 1, including abdominal cramps and nausea, followed by neurological manifestations such as hyperesthesia in the lower extremities, urinary retention, and flaccid paralysis starting November 5. The paralysis ascended rapidly, affecting the upper body and leading to respiratory failure; Brebner died on November 8, 1932, from respiratory paralysis complicated by pulmonary edema.^[7] The neurological symptoms, including ascending myelitis and paralysis after a primate bite, initially raised suspicions of rabies, a common zoonotic concern at the time. However, postmortem examination ruled out rabies through the absence of Negri bodies and incompatible histopathological findings, shifting focus to an unidentified viral agent. In 1934, Albert B. Sabin and Arthur M. Wright isolated the causative virus from Brebner's autopsy tissues, specifically emulsions of the brain, spinal cord, and spleen preserved in glycerol. These tissues were inoculated intracerebrally and intratesticularly into rabbits, yielding a filterable agent that reproduced a similar acute ascending myelitis. The virus was designated "B virus" in reference to Brebner, marking the first documented human case and isolation of this pathogen.^[7]^[8]^[9] Early experiments by Sabin and Wright confirmed the virus's neurotropic properties and herpesvirus affiliation through serial passages in animal models. Intracerebral inoculation into rabbits produced flaccid paralysis and death within 5–7 days, with the virus maintaining virulence over at least 15 passages; similar results occurred via intratesticular routes, leading to generalized infection. Attempts to passage in rhesus monkeys, mice, guinea pigs, and dogs were less consistent, but successful transmissions in rabbits revealed characteristic intranuclear inclusion bodies in neural and ganglionic tissues—hallmarks of herpesviruses observed microscopically. These inclusions, along with the virus's cytopathic effects and latency potential, aligned it closely with herpes simplex virus (HSV-1), yet cross-protection tests indicated it was immunologically related but distinct, lacking full neutralization by anti-HSV sera and exhibiting unique host range preferences. This established B virus as a novel alphaherpesvirus separate from human HSV-1.^[7]^[10]

Key developments and cases

Following the initial identification of B virus in the early 1930s, serological surveys conducted in the 1950s and 1960s among wild macaque populations in Asia and captive colonies revealed high seroprevalence rates, reaching up to 80% in some groups of adult rhesus and other macaque species, underscoring the virus's endemic nature in these primates.^[11]^[12] These studies, which utilized neutralization assays and virus isolation techniques, highlighted the latent infection patterns and intermittent shedding, informing early biosafety protocols for primate research.^[12] The case fatality rate for human B virus infections declined from approximately 80% in untreated cases before 1987 to around 40% thereafter, primarily due to the introduction of acyclovir as an antiviral therapy, which inhibits viral DNA polymerase and has been administered intravenously in exposed individuals.^[13]^[14] As of 2025, approximately 50 human cases have been documented worldwide since 1932, resulting in 21 deaths, with most infections linked to occupational or pet-related exposures rather than community spread.^[6] Notable incidents include the 1987 cluster at a research facility in Pensacola, Florida, where four individuals were exposed through monkey bites and handling, leading to one death from encephalomyelitis despite supportive care; this event marked the first confirmed human-to-human transmission via a kiss from an infected spouse.^[15] Another significant case occurred in 1998 in Texas, involving a fatal infection from a pet macaque bite, emphasizing risks from private ownership.^[16] No major outbreaks have been reported from 2021 to 2025, though isolated fatal cases, such as one in China in 2021 and another in Hong Kong in 2024, highlight persistent dangers in research and wildlife interaction settings.^[17]^[6] In response to rising concerns, the CDC established the B Virus Working Group in 1999 to enhance case tracking, develop standardized diagnostic protocols, and update prevention guidelines, building on earlier 1988 recommendations and leading to comprehensive 2002 updates that emphasize post-exposure prophylaxis with antivirals.^[18]^[9] This ongoing effort has improved surveillance and reduced mortality through timely intervention, though the virus remains a biosafety level 4 concern in primate-handling environments.^[9]

Virology

Structure

The B virus, or Cercopithecine herpesvirus 1 (CeHV-1), exhibits the characteristic morphology of alphaherpesviruses, featuring an enveloped icosahedral virion approximately 150-200 nm in diameter.^[19]^[20] The outer lipid envelope, derived from the host cell membrane, is studded with glycoprotein spikes that facilitate viral interactions with host cells.^[10] Beneath the envelope lies an amorphous tegument layer composed of viral proteins that support virion assembly and function.^[10] The capsid displays T=16 icosahedral symmetry and consists of 162 capsomers arranged in a structure measuring 100-110 nm in diameter, as visualized by electron microscopy.^[21]^[19] This nucleocapsid encloses the viral core, which contains the double-stranded DNA genome.^[10] The tegument includes key proteins such as UL41, the virion host shutoff protein, which contributes to the regulation of host cellular processes upon infection.^[22] Prominent among the envelope glycoproteins are gB, gD, and the gH/gL complex, which mediate attachment and membrane fusion during entry.^[23] These glycoproteins share substantial amino acid sequence homology with their herpes simplex virus 1 (HSV-1) counterparts, including approximately 80% identity for gB and 57% for gD.^[23] Electron micrographs confirm the overall architecture, showing the electron-dense icosahedral nucleocapsid enveloped by the tegument and lipid bilayer with surface projections.^[20]

Genome

The B virus genome is a linear double-stranded DNA molecule approximately 157 kilobase pairs (kbp) in length, encoding approximately 70-80 open reading frames (ORFs) that produce around 70 proteins.^[24]^[17] Like other alphaherpesviruses, it consists of a unique long region (UL, approximately 145 kbp) and a unique short region (US, approximately 12 kbp), with the US flanked by inverted repeat sequences (RS and TRS); the overall G+C content is high at about 74.5%, exceeding that of related human herpes simplex viruses (HSV-1 and HSV-2).^[24]^[17] The genome organization is collinear with those of HSV-1 and HSV-2, facilitating comparative analyses that highlight both conserved and divergent features.^[24] Key genes include conserved herpesvirus elements essential for replication and structure, such as the DNA polymerase encoded by UL30 and the thymidine kinase encoded by UL23, which share high amino acid sequence identity (up to 79%) with their HSV counterparts.^[24] B virus also retains homologs of genes like UL39, which encodes the small subunit of ribonucleotide reductase involved in nucleotide metabolism, supporting viral DNA synthesis.^[24] Notably, however, it lacks a homolog of the HSV-1 γ134.5 gene, a neurovirulence factor that modulates host protein synthesis and antiviral responses in HSV infections.^[24] The first complete genome sequence of B virus was determined in 2003 from the rhesus macaque isolate E2490 (GenBank accession AF533768), revealing a total length of 156,789 bp.^[24] Subsequent sequencing of additional strains has shown minimal genetic variation between wild-type and laboratory-adapted isolates, with differences primarily in non-coding repetitive regions rather than protein-coding sequences; coding regions exhibit high conservation, with most nucleotide substitutions being synonymous and not altering amino acid sequences.^[24]^[25]

Epidemiology

Prevalence in non-human primates

The B virus, also known as cercopithecine herpesvirus 1 (CeHV-1), is a natural pathogen primarily hosted by Old World macaque monkeys of the genus Macaca, where it establishes lifelong latent infections following primary exposure, typically through oral or vesicular lesions in infancy or early juvenile stages.^[10]^[26]^[27] Seroprevalence rates in adult wild rhesus macaques (Macaca mulatta) and cynomolgus macaques (M. fascicularis, also known as long-tailed macaques) range from 70% to 100%, reflecting widespread endemic infection in these populations; for instance, studies have reported 82% seropositivity in rhesus macaques from Cayo Santiago and 78.5% in wild cynomolgus macaques across Thailand.^[11]^[5] In contrast, juveniles exhibit significantly lower rates, around 10-30%, as infection often occurs post-weaning through close contact or sexual transmission upon reaching maturity.^[5]^[20] Geographically, B virus is endemic to the native range of macaques in South and Southeast Asia, with no evidence of natural infection in New World monkeys or other non-macaque species outside of artificial cross-exposure scenarios.^[28]^[20] The global risk arises from imported captive macaques used in research, where seroprevalence in adult populations can reach 73-100%, facilitating potential zoonotic spread.^[29] Infected macaques typically remain asymptomatic carriers, with intermittent viral shedding from oral secretions triggered by stressors such as immunosuppression or environmental changes, though the frequency of shedding is generally low.^[10]^[30]^[5]

Human case statistics

Since its initial identification in 1932, there have been approximately 51 laboratory-confirmed cases of human B virus (cercopithecine herpesvirus 1) infection documented worldwide, with 22 fatalities resulting in a case fatality rate (CFR) of about 43%.^[1] The vast majority of these cases—around 45—have occurred in the United States, with the remainder reported in Europe (primarily the United Kingdom and Canada) and more recently in Asia (including China and Hong Kong). In 2024, Hong Kong reported its first fatal human case, involving a 37-year-old man scratched by wild long-tailed macaques during a hiking trip in a country park, who died approximately four months after exposure despite antiviral treatment.^[9]^[31]^[6]^[32] Demographically, human B virus infections predominantly affect individuals in occupational settings, such as laboratory researchers, veterinarians, and animal handlers working with macaques, accounting for about 90% of cases; rare instances involve pet macaque exposures or tourists interacting with wild primates.^[14] Affected individuals are typically aged 20 to 60 years, with a slight predominance among males, reflecting the gender distribution in high-risk professions involving non-human primates.^[33] Temporally, roughly 25 cases were reported before 1987, when the CFR was nearly 80% due to lack of effective treatments; the subsequent approximately 26 cases after 1987 have shown a reduced CFR, attributable to prompt antiviral therapy such as acyclovir.^[30] According to CDC surveillance, no new human cases have been reported in the United States from 2021 through 2025.^[2] Among risk factors, approximately 80% of transmissions to humans result from macaque bites or scratches that introduce virus-laden saliva or tissue into wounds, with higher incidence observed in research facilities utilizing imported rhesus or other macaque species.^[20]

Transmission

From primates to humans

The primary mode of B virus transmission to humans is zoonotic, occurring from infected macaque monkeys, particularly species like rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques, which serve as the natural reservoir.^[34] These primates often harbor the virus asymptomatically or with mild symptoms, shedding it intermittently in oral secretions, saliva, or vesicular fluids, especially under stress or during primary infection.^[35] Human infections are rare, with over 50 documented cases worldwide since the first identification in 1932, primarily linked to occupational exposure in research, veterinary, or entertainment settings involving macaques, though recent cases have involved non-occupational contact with wild macaques, such as the first confirmed infection in Hong Kong in 2024 from a monkey bite during a park visit.^[34]^[5] Direct contact represents the most frequent transmission route, accounting for the majority of cases through bites or scratches that introduce virus-laden saliva or blood into the wound.^[34] Bites, in particular, are implicated in over half of reported incidents, as the mechanical injury facilitates rapid viral entry into deeper tissues.^[35] Percutaneous injuries, such as needlestick punctures or cuts from contaminated instruments like cage wires or scalpels used in primate handling, also pose significant risk by delivering infected body fluids directly into the bloodstream.^[36] Mucocutaneous exposure occurs when infectious materials from macaques contact mucous membranes or broken skin, such as splashes of oral secretions or vesicular fluid into the eyes, mouth, or nose.^[37] This pathway is well-documented in laboratory accidents, including a fatal 1997 case where a researcher's eye was exposed to macaque fluid during cell culture processing.^[34] Transmission through intact skin is rare, requiring breaches that allow viral penetration, as the virus does not efficiently cross unbroken barriers.^[35] Indirect transmission via fomites is possible in controlled environments like laboratories or primate facilities, where the virus contaminates surfaces, caging materials, or equipment with moist secretions.^[36] The incubation period following exposure typically ranges from 3 to 30 days, with an average of 10 to 14 days in most documented cases, during which the virus may travel along sensory nerves to establish infection.^[37] No evidence supports airborne or foodborne spread, as the virus lacks mechanisms for aerosolization or gastrointestinal persistence.^[34] B virus exhibits low environmental stability outside the host, surviving only hours on moist surfaces and rapidly inactivating upon drying or exposure to common disinfectants like 70% ethanol or sodium hypochlorite.^[36] This fragility limits indirect transmission but underscores the importance of immediate wound cleansing and barrier precautions in high-risk settings.^[35]

Rare human-to-human spread

Human-to-human transmission of B virus (Cercopithecine herpesvirus 1) is exceedingly rare, with only a single confirmed case documented to date. This incident occurred in 1990 in the United States, involving a laboratory worker's spouse. The husband, who had acquired B virus through occupational exposure to infected macaques, developed vesicular skin lesions containing the virus. His wife applied hydrocortisone cream contaminated with material from his lesions to her own skin affected by contact dermatitis and to her eyes, resulting in her infection; B virus was subsequently isolated from her skin lesions and conjunctiva. She did not develop systemic disease but required antiviral treatment, and no further transmission occurred from her.^[38] Potential routes for human-to-human spread are limited to direct contact with infectious bodily fluids or tissues, such as saliva, vesicular fluid from lesions, or neural tissue, typically requiring breaks in the skin or mucous membrane exposure in close-contact scenarios. However, beyond the index case, no other instances of secondary transmission have been verified, and there are no reports of sexual, respiratory, or casual contact leading to infection. This scarcity underscores the virus's poor adaptation to human hosts compared to its natural reservoir in macaques.^[34]^[39] As of 2025, no additional human-to-human cases have been reported, with all over 50 documented human infections since 1932 tracing directly to primate exposure. This pattern reinforces the primarily zoonotic nature of B virus and the absence of sustained community transmission, guiding public health surveillance toward occupational and primate-handling risks rather than interpersonal spread.^[34]^[40]

Pathogenesis and clinical features

In non-human primates

In non-human primates, B virus primarily infects macaque species, where it causes a typically mild or subclinical infection that establishes lifelong latency. Primary infection often occurs in infants and juveniles through oral contact, leading to vesicular lesions on the oral mucosa or gingiva that resolve within 2-3 weeks without significant morbidity.^[10]^[41] Following resolution, the virus establishes latency in the trigeminal ganglia, as well as lumbosacral sensory ganglia, where it persists without active replication.^[42]^[43] Reactivation in adult macaques is usually asymptomatic, occurring intermittently in response to stressors such as transportation, social challenges, or immunosuppression, resulting in brief viral shedding from oral, nasal, or genital mucosa for hours to days.^[17]^[41] However, in immunocompromised or co-infected individuals, reactivation can lead to severe disease, including disseminated infection with encephalitis, though such fatal central nervous system involvement affects less than 1% of adults in typical populations.^[44]^[10] Pathologically, active B virus infection in macaques manifests as vesicular lesions with mucosal ulceration, necrosis, and mild fever, often resolving spontaneously.^[45] Vertical transmission is rare, with maternal antibodies providing temporary passive protection to offspring rather than direct in utero or perinatal spread.^[17] Unlike in humans, macaques do not exhibit chronic shedding, maintaining intermittent, stress-induced patterns instead. Species variations exist, with rhesus macaques (Macaca mulatta) showing more frequent symptomatic presentations, such as oral vesicles in approximately 2.3% of cases, compared to generally milder or less observable disease in cynomolgus macaques (Macaca fascicularis).^[17]^[10]

In humans

B virus infection in humans typically has an incubation period of 3 to 30 days following exposure, during which individuals may remain asymptomatic.^[1] Early signs often mimic influenza, including fever, fatigue, headache, and muscle aches, accompanied by local symptoms such as vesicular lesions or erythema at the exposure site if the inoculation was cutaneous.^[9] Additional nonspecific features can include lymphadenitis, nausea, hiccups, and sore throat, appearing within the first week post-incubation.^[44] The disease frequently progresses to a severe neurological phase, characterized by ascending myelitis or encephalitis, with symptoms emerging 1 to 21 days after initial signs.^[1] This phase involves hyperesthesia, paresthesia, ataxia, diplopia, agitation, flaccid paralysis, and seizures, as the virus ascends along peripheral nerves to the central nervous system.^[9] Respiratory failure, often due to diaphragmatic paralysis, is the leading cause of death in affected individuals.^[44] In rare atypical presentations, cases may manifest as isolated dermatitis, conjunctivitis, or ocular involvement without central nervous system progression, though such limited disease is uncommon. Rare cases of reactivation have also been documented, including severe meningoencephalitis occurring 54 years after initial infection.^[17]^[46] Overall fatality approaches 40-50% even with antiviral treatment, in over 50 documented cases since 1932, with most deaths occurring from encephalomyelitis despite supportive care.^[1] Survivors frequently experience permanent neurological deficits, including neuropathy and motor impairment.^[14] Autopsy findings in fatal cases reveal necrotizing myelitis with inflammation and necrosis in the spinal cord, brainstem, and occasionally visceral organs, along with eosinophilic intranuclear viral inclusions in neurons.^[17]

Diagnosis

Laboratory methods

Polymerase chain reaction (PCR) serves as the primary method for direct detection of B virus (Cercopithecine herpesvirus 1) DNA in clinical specimens, including cerebrospinal fluid (CSF), lesion swabs, biopsies, and neural tissues, offering rapid results compared to traditional culture techniques.^[4] Real-time quantitative PCR (qPCR) assays target conserved genomic regions such as the glycoprotein B (gB) gene or the DNA polymerase gene, enabling specific identification and differentiation from related alphaherpesviruses like herpes simplex virus (HSV).^[47]^[48] These assays demonstrate high sensitivity, with limits of detection as low as 35 viral genome copies in tissue samples, and are performed in specialized laboratories to minimize biosafety risks associated with potentially viable virus.^[47]^[49] Serological testing detects anti-B virus IgM and IgG antibodies through enzyme-linked immunosorbent assay (ELISA) or Western blot, utilizing recombinant viral antigens to enhance specificity and reduce cross-reactivity with HSV.^[50]^[51] Confirmatory plaque reduction neutralization tests measure functional antibody titers by assessing serum-mediated inhibition of viral plaque formation in cell culture, providing evidence of protective immunity.^[4]^[52] However, serology is typically employed retrospectively, as antibody responses may take weeks to develop post-exposure and are less reliable for acute diagnosis.^[35] Virus isolation, while historically the diagnostic gold standard, is infrequently pursued due to the necessity of biosafety level 4 (BSL-4) containment to prevent laboratory-acquired infections.^[4] When conducted, specimens are inoculated onto Vero cell monolayers, where B virus replication induces characteristic cytopathic effects, including cell rounding, syncytium formation, and detachment, observable within 3 to 7 days.^[35] In postmortem examinations, immunohistochemistry on fixed brain tissue identifies B virus antigens in neural cells, facilitating confirmation of encephalitic involvement in fatal human cases.^[35] This technique complements molecular methods by localizing viral proteins in affected tissues, though it requires well-preserved samples for optimal antigen detection.^[50]

Differential considerations

B virus infection in humans often presents with flu-like symptoms progressing to vesicular lesions at the exposure site, followed by neurological complications such as ascending flaccid paralysis and encephalitis, which can mimic several other conditions. Differential diagnosis relies heavily on exposure history, particularly contact with macaques, combined with specific laboratory testing to confirm or rule out B virus while excluding alternatives. Early differentiation is crucial due to the high fatality rate of untreated B virus (approximately 80%) and the availability of post-exposure prophylaxis.^[1] Rabies shares features with B virus, including ascending paralysis and encephalomyelitis following animal exposure, but typically involves wild carnivores or bats rather than macaques, and lacks initial vesicular skin lesions. Differentiation is achieved through exposure history (macaque contact favoring B virus) and targeted testing: negative PCR or serology for rabies virus RNA/antibodies, contrasted with positive B virus PCR detecting Macacine herpesvirus 1 DNA in lesion swabs or cerebrospinal fluid (CSF). Rabies immunofluorescence on brain tissue (if fatal) would be negative in B virus cases.^[20]^[53] Herpes simplex virus (HSV-1/2) encephalitis can present with similar central nervous system (CNS) symptoms like headache, fever, and altered mental status, often with oral or genital vesicles, but without the primate exposure link. B virus is distinguished by macaque bite or scratch history and molecular testing: while glycoprotein B (gB) sequences show homology between B virus and HSV, real-time PCR assays targeting B virus-specific regions (e.g., UL27/gB or gG genes, yielding 209 bp amplicons) are negative for HSV primers, and virus isolation in cell culture (e.g., Vero cells) confirms B virus cytopathic effects distinct from HSV. Serologic assays using B virus glycoprotein D (gD) or monoclonal antibodies to mgG further resolve cross-reactivity issues.^[9]^[20] West Nile virus or enterovirus infections may cause fever, myalgia, and encephalitis with flaccid paralysis, resembling B virus CNS involvement, but are associated with arthropod vectors or fecal-oral transmission rather than primate contact. Rule out via exposure history (mosquito/bird for West Nile, gastrointestinal symptoms for enterovirus) and specific serology: absence of West Nile IgM in serum/CSF or enterovirus VP1 PCR, alongside negative B virus culture or PCR from lesions/CSF. CSF analysis may show overlapping lymphocytic pleocytosis, but B virus-specific viral load via quantitative PCR provides definitive distinction.^[54]^[20] Bacterial cellulitis or tetanus initially mimic the local wound complications of B virus, with erythema, swelling, or pain at the bite site, but lack progression to vesicles or neurological symptoms like ascending paralysis. Bacterial cellulitis (e.g., from Pasteurella or Staphylococcus) responds to antibiotics and shows positive wound cultures for bacteria without viral cytopathic effects, while tetanus features muscle spasms and rigidity without fever or vesicles, confirmed by clinical history (unvaccinated wound) and absence of B virus DNA by PCR. In both, the rapid evolution to neuroinvasive disease and positive B virus testing (e.g., from swabbed vesicles) differentiate it, emphasizing viral etiology over bacterial.^[55]^[20]

Prevention

Occupational and laboratory safety

Occupational and laboratory safety measures are essential for preventing B virus (Herpesvirus simiae) exposure among personnel working with macaque monkeys or their tissues in research, veterinary, or zoological settings, given the virus's high prevalence in these primates—80-96% in adults, varying by population and setting—and its potential for severe zoonotic transmission through bites, scratches, or mucosal contact.^[30]^[5] These protocols emphasize engineering controls, personal protective equipment (PPE), and administrative practices to minimize direct contact, as B virus shedding can occur intermittently even in asymptomatic carriers.^[2] No vaccine is currently available to prevent B virus infection in humans or nonhuman primates as of 2025.^[1] Personal protective equipment is mandatory for all activities involving macaques or potentially infected materials to create a barrier against bodily fluids and tissues. Standard PPE includes laboratory coats or gowns, cut-resistant gloves (such as arm-length reinforced leather or heavy-duty nitrile), face shields or surgical masks combined with goggles for splash protection, and closed-toe shoes; additional layers like aprons may be required during procedures.^[30]^[36] Double-gloving with a cut-resistant outer layer over a disposable inner glove is recommended for high-risk tasks, such as invasive procedures or necropsies, to enhance puncture resistance and allow for immediate detection of breaches.^[56] Work with confirmed infected tissues or fluids requires Biosafety Level 2+ (BSL-2+) containment, incorporating enhanced practices like restricted access and secondary barriers beyond standard BSL-2.^[57] Facility protocols focus on reducing the introduction and spread of B virus within primate colonies. Incoming macaques should undergo seroscreening using enzyme immunoassay or PCR to detect antibodies or viral DNA, with seropositive animals placed in quarantine for at least 30 days and monitored for clinical signs like oral lesions; in some research programs, euthanasia of confirmed positives is performed to maintain B virus-free breeding colonies, though this is not universally required.^[30] Quarantine facilities must feature squeeze-back cages or other restraint mechanisms to limit handling of awake animals, and chemical sedation (e.g., ketamine) is preferred over manual restraint to avoid bites or scratches.^[30] All macaques, regardless of serostatus, should be treated as potentially infectious due to latent infections and stress-induced reactivation.^[58] Training programs are critical for personnel, providing education on B virus transmission risks—primarily through percutaneous or mucocutaneous exposure during primate handling—and emphasizing safe practices like minimizing direct contact and using tools for feeding or sample collection.^[30] Workers must receive annual refreshers on PPE donning/doffing, incident reporting, and recognition of exposure risks, with immediate supervisor notification required for any potential contact to facilitate rapid assessment.^[36] Environmental decontamination protocols involve prompt cleanup of spills or contaminated surfaces using effective virucides, as B virus is an enveloped herpesvirus susceptible to lipid solvents and oxidants. A 1:10 dilution of household bleach (0.5% sodium hypochlorite) or peracetic acid (0.2%) applied for at least 10 minutes is recommended for decontaminating work areas, equipment, or caging, followed by rinsing to prevent corrosion; all waste must be autoclaved or chemically treated before disposal.^[59]^[56] Regulatory oversight classifies B virus as a Centers for Disease Control and Prevention (CDC)/National Institutes of Health (NIH) select agent under the Federal Select Agent Program, mandating registration, security plans, and incident reporting for entities possessing or transferring the virus or infected materials.^[58] Import of seropositive macaques is restricted by the CDC and U.S. Department of Agriculture, requiring permits and adherence to biosafety guidelines to prevent unintended release.^[30] Compliance with these standards, outlined in the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories manual, ensures protection in high-risk environments.^[60]

Post-exposure prophylaxis

Post-exposure prophylaxis for B virus (cercopithecine herpesvirus 1) infection focuses on immediate wound management, risk assessment, antiviral administration for high-risk exposures, and ongoing monitoring to prevent progression to clinical disease.^[61] High-risk exposures include percutaneous injuries such as bites or scratches from macaques that break the skin, particularly to the head, neck, torso, or upper extremities, as well as needlestick injuries involving neural tissue or mucosal contact; exposures from ill, immunocompromised, or virus-shedding animals further elevate risk.^[61] Immediate wound care is critical and should begin within minutes of exposure to reduce viral inoculum. For skin wounds, gently scrub the area with soap, detergent, povidone-iodine, or chlorhexidine for 15 minutes, followed by irrigation with running water for an additional 15-20 minutes; avoid high-pressure methods that could drive virus deeper into tissues.^[61] For mucous membrane exposures, such as splashes to the eyes or mouth, flush thoroughly with sterile saline or water for 15 minutes.^[61] Deep or contaminated wounds may require surgical consultation for debridement, but initial suturing should be delayed to prioritize antiviral prophylaxis and irrigation.^[61] Antiviral prophylaxis is recommended for high-risk exposures and should be initiated as soon as possible, ideally within hours and no later than 5 days post-exposure. The preferred regimen is oral valacyclovir at 1 g every 8 hours for 14 days; alternatively, oral acyclovir at 800 mg five times daily for 14 days may be used, with dosing adjustments for renal impairment.^[61] For exposures involving neural tissue or severe wounds where oral therapy is not feasible, intravenous acyclovir (12.5-15 mg/kg every 8 hours) or ganciclovir (5 mg/kg every 12 hours) for 14 days is an option, though oral agents are generally sufficient for prophylaxis without central nervous system involvement.^[61] All exposed individuals, whether receiving prophylaxis or not, require close monitoring for symptoms of infection, including local wound erythema, vesicles, pain, numbness, or systemic signs such as fever, headache, or neurological deficits, which can appear 1-30 days post-exposure.^[61] Daily self-monitoring for symptoms is advised for the first 30 days, with clinical follow-up visits at 1, 2, and 4 weeks; any suggestive symptoms warrant immediate evaluation and potential diagnostic testing. Serologic testing for B virus antibodies should include baseline collection at exposure (if feasible), followed by paired samples at 14-21 days, 30 days, and 90 days post-exposure to detect seroconversion, with positives confirmed via Western blot or specific assays due to cross-reactivity with herpes simplex virus; specimens should be sent to specialized laboratories such as the National B Virus Resource Center at Georgia State University.^[4] Exposures should be reported promptly to occupational health providers, local health departments, and the CDC for coordination of care, testing, and public health response, using contact protocols established for B virus incidents.^[61] Standard wound management also includes updating tetanus prophylaxis if immunization is not current, and assessing for rabies post-exposure prophylaxis based on the exposure circumstances and animal status, though B virus remains the primary concern in macaque-related incidents.

Treatment

Antiviral therapy

The first-line antiviral therapy for active B virus (Cercopithecine herpesvirus 1) infection in humans is intravenous acyclovir at a dose of 12.5–15 mg/kg every 8 hours for 14–21 days, particularly in cases without central nervous system (CNS) involvement; this regimen reduces viral replication despite the drug's poor penetration into cerebrospinal fluid.^[61]^[13] For infections with CNS symptoms, ganciclovir (5 mg/kg intravenously every 12 hours) is preferred due to its better efficacy against B virus, though acyclovir remains an option if ganciclovir is unavailable.^[13] Alternatives include ganciclovir or foscarnet for rare acyclovir-resistant strains, while oral valacyclovir (1 g every 8 hours) may be used for milder cases without CNS involvement.^[61]^[13] Prompt antiviral therapy has reduced the case fatality rate to approximately 20% from 70-80% in untreated cases, with optimal outcomes when initiated within 48 hours of symptom onset.^[62] Treatment requires monitoring of renal function due to potential nephrotoxicity, with dose adjustments as needed.^[61] Challenges in therapy include B virus's reduced sensitivity to acyclovir compared to herpes simplex virus type 1, reflected in a higher half-maximal inhibitory concentration (IC₅₀) of approximately 18 μg/mL versus 1–2 μg/mL for HSV-1; ganciclovir shows better activity with an IC₅₀ of about 9 μg/mL.^[13] As of 2025, no antiviral drugs are specifically approved by the FDA for B virus infections, and all treatments are used off-label based on extrapolations from animal models and limited human case data.^[61]^[13]

Supportive care

Supportive care plays a critical role in managing B virus (cercopithecine herpesvirus 1) infections in humans, focusing on organ support and complication prevention alongside antiviral therapy to enhance survival and mitigate long-term effects.^[1] Patients with severe disease, particularly those developing central nervous system involvement, require intensive care unit (ICU) monitoring to address life-threatening complications such as respiratory failure, which arises from ascending paralysis and represents the leading cause of death in fatal cases.^[1] Mechanical ventilation is often necessary for respiratory compromise, occurring within 1 day to 3 weeks after symptom onset.^[1] In cases of encephalitis, supportive measures include anticonvulsant administration to control seizures, a common manifestation that can exacerbate neurologic damage.^[63] Initial wound management emphasizes thorough irrigation and debridement if needed, following exposure to prevent viral entry and secondary bacterial infection; for subsequent vesicular lesions at the site of inoculation, local care involves gentle cleansing and protection to promote healing without rupture.^[61] Systemic corticosteroids are generally avoided, as immunosuppression may facilitate viral dissemination and worsen outcomes in active herpesvirus infections.^[64] Survivors of B virus infection frequently face significant long-term challenges, necessitating multidisciplinary rehabilitation. Physical therapy is essential for addressing peripheral neuropathy, paresis, or paralysis resulting from neural damage, with inpatient programs often extending several weeks to restore function.^[46] Psychological support is recommended to help manage the emotional impact of occupational exposure and severe illness, particularly in laboratory or research settings.^[16] The prognosis for B virus infection remains grave, though early intervention with antivirals and supportive care has reduced fatality from historical untreated levels of 70-80%. Most survivors (over 70%) experience permanent neurologic deficits, such as paralysis or cognitive impairment, underscoring the need for ongoing supportive interventions.^[1]^[65]

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