Discovery of naturally occurring transmissible chronic hepatitis B virus infection amongMacaca fascicularisfrom mauritius island

Abstract

Despite a high prevalence of hepatitis B virus (HBV) infection in endangered apes, no HBV infection has been reported in small, old-world monkeys. In search for a small, nonhuman primate model, we investigated the prevalence of HBV infection in 260 macaque (Cercopithecidae) sera of various geographical origins (i.e., Morocco, Mauritius Island, and Asia). HBV-positive markers were detected in cynomolgus macaques (Macaca fascicularis) from Mauritius Island only, and, remarkably, HBV DNA was positive in 25.8% (31 of 120) and 42% (21 of 50) of serum and liver samples, respectively. Strong liver expression of hepatitis B surface antigen and hepatitis B core antigen was detected in approximately 20%-30% of hepatocytes. Furthermore, chronic infection with persisting HBV DNA was documented in all 6 infected macaques during an 8-month follow-up period. Whole HBV genome-sequencing data revealed that it was genotype D subtype ayw3 carrying substitution in position 67 of preS1. To confirm infectivity of this isolate, 3 Macaca sylvanus were inoculated with a pool of M. fascicularis serum and developed an acute HBV infection with 100% sequence homology, compared with HBV inoculum. We demonstrated the presence of a chronic HBV infection in M. fascicularis from Mauritius Island. This closely human-related HBV might have been transmitted from humans, because the initial breeding colony originated from very few ancestors 300 years ago when it was implemented by Portuguese who imported a handful of macaques from Java to Mauritius Island. Conclusion: This report on natural, persisting HBV infection among cynomolgus macaques provides the first evidence for the existence of a novel, small simian model of chronic HBV infection, immunologically close to humans, that should be most valuable for the study of immunotherapeutic approaches against chronic hepatitis B. (HEPATOLOGY 2013;58:1610-1620 See Editorial on Page 1533 D espite the existence of an effective vaccine, chronic hepatitis B virus (HBV) infection remains a major public health problem, responsible for 55% of hepatocellular carcinomas worldwide. Current chronic hepatitis B (CHB) treatments (e.g., interferon and nucleos(t)ide analogs) remain long lasting, expensive, partially efficient (25%), and frequently lead to the emergence of

Origins and Evolution of Hepatitis B Virus and Hepatitis D Virus

“…This is supported by the finding that geographical regions with potentially high HBV transmission rates between human and nonhuman primates are also areas of high HBV prevalence among humans (i.e., Southeast Asia and Africa). There are several reports of known cross-species transmission cases, such as human HBV identified from chimpanzees (Hu et al 2000;Takahashi et al 2000), the identification of human/primate HBV recombinants (Magiorkinis et al 2005;Simmonds and Midgley 2005), infection of Mauritian macaques with human HBV (Dupinay et al 2013), and a gibbon variant isolated from a chimpanzee (Grethe et al 2000), which would lend substantial credence to this model.…”

The Chimpanzee Model for Hepatitis B Virus Infection

“…Reports that HBV could also be transmitted to, and serially passaged in, rhesus monkeys could not be confirmed (London et al 1972). Similarly, a more recent report showed HBV replication in a Barbary macaque (Macaca sylvanus) after transfection of cloned HBV DNA, but serial passage and persistent infection in these animals was not observed (Gheit et al 2002;Dupinay et al 2013). In contrast, gibbons (genus Hylobates) at the International Center for Gibbon Studies (Santa Clarita, CA) were positive for markers of ongoing or past HBV infection and phylogenetic analysis of the isolated HBV sequences suggested that the gibbons, most likely, had been infected by transmission of HBV from humans (Lanford et al 2000).…”

“…This observation is consistent with two previous studies, providing serological evidence of HBV infection in gibbons inoculated with human HBsAgpositive saliva or semen (Bancroft et al 1977;Scott et al 1980). Finally, it was shown that a Macaca fascicularis colony from Mauritius Island was naturally infected with a human HBV isolate (Dupinay et al 2013). Macaques might become an alternative model to chimpanzees for the study of therapeutic approaches against HBV infections (Bukh et al 2013).…”

“…In the early 1970s, it was shown that chimpanzees were fully susceptible to infection with HBV present in human plasma (Maynard et al 1972;Barker et al 1973). Much later, HBV strains indigenous to chimpanzees and other nonhuman primates were discovered (Norder et al 1996;Lanford et al 1998Lanford et al , 2000Warren et al 1999;Grethe et al 2000;Hu et al 2000Hu et al , 2001MacDonald et al 2000;Takahashi et al 2000Takahashi et al , 2001Vartanian et al 2002;Sall et al 2005;Dupinay et al 2013). In 1977, the HBV-associated delta antigen was identified in patients (Rizzetto et al 1977).…”

Antiviral Therapies and Prospects for a Cure of Chronic Hepatitis B

“…Improvement of these models is now in progress with genetic engineering of mouse lineage to express hNTPC, as well as to engineer doubly humanized mice for both human hepatocytes and the human immune system. The development of more robust cell culture models and small primate models to recapitulate HBV infection and its pathogenesis is also highly desirable (Dupinay et al 2013;Shlomai et al 2014). …”