Herpes B Sequence Variation in Captive Macaques: Did Human Agency Contribute to the Emergence of a Highly Pathogenic Herpes B virus in the Biomedical Laboratory?

The genus Macaca is the most ecologically successful and widely distributed nonhuman primate (NHP) taxon. Like other NHP, macaques are naturally infected with their own complement of herpesviruses analogous to their human counterparts. (Estep et al.,2010) The macaque alpha-herpesvirus (Macacine alphaherpesvirus 1; monkey B virus, BV) is closely related to the human herpes simplex viruses HSV1 and HSV2. In macaques BV infection can be oral and/or genital, is usually asymptomatic, the virus establishes latency in sensory ganglia, and various forms of stress can result in reactivation of BV from latency and shedding of infectious virus in bodily secretions. (Huff et al., 2003; Huff and Barry, 2003; Keeble, 1960; Weigler, 1992) A few studies have shown that free-ranging macaques in habitat countries are seropositive for BV, but the genetic diversity of BV in naturally occurring macaque populations has not been investigated. (Engel et al., 2002, 2008; Jones-Engel et al., 2006; Lee et al., 2015). While BV rarely causes serious disease in healthy adult macaques, when transmitted to humans or other primate species BV can be neuropathogenic. Only about 50 cases of zoonotic BV infection, all of which have occurred in the context of exposure to laboratory or captive animals, have been documented since the virus was first recognized in 1932, but most (~75%) have been lethal. (Davidson and Hummeler, 1960; Huff and Barry, 2003; Palmer, 1987; Weigler, 1992) The high mortality associated with zoonotic BV infection makes this virus the single most serious zoonotic concern for animal care and research personnel working with or around macaque monkeys. Prior to the 1950's, NHPs were wild caught in habitat countries and shipped to the USA for use in research. In the late-1950's, concerns over the lack of macaques available to import for biomedical research as well as a desire to explore the utility of other NHP species for research led to the development through the National Institutes of Health of seven National Primate Research Centers (NPRC) in the US. These Centers, established in 1960–1965, maintained breeding colonies of 45 different NHP species. At this time, husbandry concerns surrounding potential cross-species transmission of infectious agents in these heterogeneous NHP colonies were largely underappreciated as the focus was on biomedical research on human diseases. (Anonymous,1971; Gibson, 1994) Over the next five decades tens of thousands of NHP of diverse taxa were imported, bred and transferred between facilities. Consequently, many macaques, particularly Indian-originrhesus used in research today, have been bred for generations in captivity. When the founder animals of current captive breeding colonies were originally imported, it was common practice among capture teams to co-house monkeys of different species, and infectious disease outbreaks often caused significant losses of newly captured monkeys. Thus, it is possible that some BV isolates from captive macaques could in fact reflect viruses that are not natural to the host or even chimeric/recombinant viruses resulting from the practice of cohousing multiple taxa of NHP in captive environments. All these factors need to be borne in mind when assessing genetic diversity among viral isolates.