Macaque herpesvirus (B virus, BV)

B virus (macaque herpesvirus, BV) is taxonomically classified within the alphaherpesvirus subfamily and the genus Herpes simplex. B virus has only one serotype and shares close antigenic relationships with baboon herpesvirus type 2, human herpes simplex virus (HSV), and African green monkey herpesvirus (SA8). B virus is sensitive to lipid solvents, susceptible to heat, and can also be effectively inactivated by ultraviolet light.

The natural host of B virus is the rhesus monkey. Infected and asymptomatic carrier monkeys serve as significant sources of infection, as the virus can intermittently shed from the animals' saliva, semen, and other bodily fluids. A key feature of B virus is its ability to establish latent infections, often hiding in nerve ganglia near the respiratory tract and urogenital organs. While such infections typically remain silent in the host, they can reactivate under certain triggering conditions, leading to rapid viral replication and subsequent transmission to new individuals. Animals primarily contract B virus through scratches, bites, close contact, or sexual behavior; consequently, adult monkeys generally exhibit much higher rates of BV positivity compared to younger ones.

All macaques appear to carry BV, but the BV strains isolated from different species and geographic regions of macaques exhibit molecular-level differences. Since research on the biological characteristics of B virus remains limited, whether these differences also exist at the biological level has yet to be reported.

Multiple studies have shown that herpes viruses co-evolve with their hosts. Analysis reveals that each species of non-human primate (NHP) harbors its own unique α-herpesvirus, which shares genetic and antigenic similarities with existing herpesviruses. Typically, these herpes viruses remain asymptomatic in their natural hosts. However, if they cross species barriers and infect other NHPs, they can trigger more severe clinical symptoms—and in many cases, even lead to animal fatalities. For instance, numerous studies have documented human herpes simplex virus (HSV) transmission to various NHP species, with some cases resulting in animal deaths. Similarly, B virus, transmitted from macaques to other New World monkeys, has also been linked to fatal outcomes. Moreover, squirrel monkey herpesvirus, when transmitted from its natural host—the squirrel monkey—to marmosets or owl monkeys, can cause diffuse, multifocal necrosis of internal organs, ultimately leading to the animals' demise.

Most macaques infected with B virus show no obvious clinical symptoms. However, with careful observation, localized lesions in the oral or genital areas may occasionally be detected. In herpes lesions, epithelial cells exhibit vacuolar degeneration and necrosis, along with the presence of intranuclear inclusion bodies. After entering the body by infecting mucosal epithelial cells, the virus replicates and subsequently spreads to unmyelinated sensory nerve endings within the epidermis. Ultimately, it travels via axons into neurons located in sensory ganglia. During a typical infection, the virus remains dormant within sensory neurons, maintaining a non-replicative state. Once latent infection is established, BV can reactivate and resume shedding under various stress conditions, becoming an infectious source capable of transmitting the virus to other individuals. Notably, the rate of viral shedding among normally captive macaques is very low—typically 2% to 3%—and tends to peak during the breeding season. Key factors that trigger this shedding include animal transportation, immunosuppression, and changes in cage environments.

Virus isolation is relatively uncommon, not only because the number of virus-excreting animals is limited, but also because B virus isolation requires working in a biosafety level 3 laboratory—conditions that most labs simply don't have.

The PCR method is highly sensitive and specific, but it can only detect the presence of the virus if the animal happens to be in the shedding phase at the time of sampling. Therefore, its test results cannot serve as a definitive indicator of whether an animal is infected with BV, which is why it isn’t widely used.

Once animals are infected with BV, antibodies can persist for a long time, which is why serological methods are currently the primary approach for detection. While detecting the BV antigen itself would be ideal, few laboratories are equipped to safely produce it. As a result, it’s common practice to use other herpesviruses related to B virus as antigens—most notably baboon herpesvirus type 2 (HVP2) and HSV-1 antigen. However, multiple studies have confirmed that HSV-1 exhibits relatively poor sensitivity in this context.

After human exposure, diagnosing B virus is a complex and challenging process. While antibody tests can be used for post-exposure detection, antibody production typically takes 7 to 10 days. Moreover, since most people have a history of HSV infection, cross-reactivity between BV and HSV further complicates antibody-based testing.

There are several existing distinction methods:

Use the Western Blot method to distinguish between BV- and HSV-specific proteins;

Detect antibodies in the sample after adsorbing them using HSV antigen;

Prepare specific recombinant BV proteins, etc.;

Additionally, the PCR method has been employed to directly detect BV nucleic acid in swab samples taken from wounds, as well as to test corresponding animals for evidence of viral shedding, thereby helping assess exposure risks. Although PCR's high sensitivity makes it an ideal detection tool, it’s important to recognize that there are varying degrees of genetic sequence differences among BV strains isolated from different species of NHPs—and even among BV isolates derived from rhesus monkeys sourced from different origins. Moreover, given the limited number of published BV gene sequences available, it remains challenging to fully evaluate the extent of variation among BV isolates. Consequently, primers designed for this purpose may fail to detect all BV strains. At the same time, the primers used in the testing laboratory must also exhibit sufficient specificity to distinguish BV from other herpesviruses, such as HSV.

Reports of BV infecting humans first emerged in 1932, and in the decades since, there have been sporadic cases of human B virus infections—totaling approximately 50 reported instances. The most recent human case of BV infection occurred in Japan in 2019. Given that countless professionals and non-human primates (NHPs) are exposed to the virus daily, the actual number of reported BV infections among humans remains remarkably low. Although BV infections are exceedingly rare, they can lead to extremely severe illness. Without treatment, the mortality rate for BV infection can soar as high as 70% to 80%, and even survivors often suffer from significant neurological impairments.

To date, all confirmed cases of BV infection have occurred among staff working with captive NHPs—such as animal caretakers, veterinarians, and laboratory researchers. There have been no reported cases of BV infection following contact with wild macaques. The vast majority of human BV infections are linked to macaque bites or scratches, while other confirmed transmission routes include monkey urine splashing into the eyes, needlestick injuries, contamination of wounds with primary macaque cells, and one documented case of person-to-person transmission. Among all known human cases of BV, the majority have been reported in Europe, the United States, and Canada. Meanwhile, despite hundreds or even thousands of NHP bites and scratches occurring annually in Asia, only two cases of BV infection have been recorded in Japan—and one case in Beijing.

Although the number of cases is low, their severity is high. Therefore, in the event of BV exposure, staff should follow an emergency protocol to properly treat any wounds, while simultaneously collecting samples from both humans and animals for testing to assess the risk. Additionally, preventive antiviral treatment recommendations should be provided.

Currently, the recommended treatment for BV infection is to use oral antiviral medications prophylactically, or to administer intravenous ganciclovir (GCV) if neurological symptoms appear. Both ACV (acyclovir) and GCV have been shown to effectively prevent disease progression in some cases, while proving ineffective in others. It’s important to note that once the infection progresses to involve the central nervous system, treatment options are rarely successful.

Further in-depth research on the herpesvirus in NHPs is still needed, such as investigating the molecular and biological differences among distinct BV isolates derived from macaques of different origins, as well as conducting large-scale, comprehensive epidemiological studies on BV prevalence among laboratory animal personnel, caretakers, and individuals who come into contact with wild macaques. These studies will help us better understand the true public health implications of BV for humans.

References

1. Eberle R, Jones-Engel L. Understanding Primate Herpesviruses[J]. Journal of Emerging Diseases & Virology, 2017.

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3. http://breakingnews.ws/monkey-infects-scientist-with-deadly-Herpes B virus—in the country’s first devastating infection.

4. Eberle R, Maxwell L K, Nicholson S, et al. Genome sequence variation among isolates of monkey B virus (Macacine alphaherpesvirus 1) from captive macaques[J]. Virology, 2017, 508:26-35.

5. SeveriniA, Tyler S D, Peters G A, et al. Genome sequence of a chimpanzee herpesvirus and its relationship to other primate alphaherpesviruses[J]. Archives of Virology, 2013, 158(8):1825-1828.