Complete Unique Genome Sequence, Expression Profile, and Salivary Gland Tissue Tropism of the Herpesvirus 7 Homolog in Pigtailed Macaques

Abstract

Human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 are classified as roseoloviruses and are highly prevalent in the human population. Roseolovirus reactivation in an immunocompromised host can cause severe pathologies. While the pathogenic potential of HHV-7 is unclear, it can reactivate HHV-6 from latency and thus contributes to severe pathological conditions associated with HHV-6. Because of the ubiquitous nature of roseoloviruses, their roles in such interactions and the resulting pathological consequences have been difficult to study. Furthermore, the lack of a relevant animal model for HHV-7 infection has hindered a better understanding of its contribution to roseolovirus-associated diseases. Using next-generation sequencing analysis, we characterized the unique genome of an uncultured novel pigtailed macaque roseolovirus. Detailed genomic analysis revealed the presence of gene homologs to all 84 known HHV-7 open reading frames. Phylogenetic analysis confirmed that the virus is a macaque homolog of HHV-7, which we have provisionally named Macaca nemestrina herpesvirus 7 (MneHV7). Using high-throughput RNA sequencing, we observed that the salivary gland tissue samples from nine different macaques had distinct MneHV7 gene expression patterns and that the overall number of viral transcripts correlated with viral loads in parotid gland tissue and saliva. Immunohistochemistry staining confirmed that, like HHV-7, MneHV7 exhibits a natural tropism for salivary gland ductal cells. We also observed staining for MneHV7 in peripheral nerve ganglia present in salivary gland tissues, suggesting that HHV-7 may also have a tropism for the peripheral nervous system. Our data demonstrate that MneHV7-infected macaques represent a relevant animal model that may help clarify the causality between roseolovirus reactivation and diseases.IMPORTANCE Human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 are classified as roseoloviruses. We have recently discovered that pigtailed macaques are naturally infected with viral homologs of HHV-6 and HHV-7, which we provisionally named MneHV6 and MneHV7, respectively. In this study, we confirm that MneHV7 is genetically and biologically similar to its human counterpart, HHV-7. We determined the complete unique MneHV7 genome sequence and provide a comprehensive annotation of all genes. We also characterized viral transcription profiles in salivary glands from naturally infected macaques. We show that broad transcriptional activity across most of the viral genome is associated with high viral loads in infected parotid glands and that late viral protein expression is detected in salivary duct cells and peripheral nerve ganglia. Our study provides new insights into the natural behavior of an extremely prevalent virus and establishes a basis for subsequent investigations of the mechanisms that cause HHV-7 reactivation and associated disease.

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

“…Additionally, identification of naturally occurring herpesviruses related to human roseoloviruses has been reported by various groups, notably in pig-tailed macaques (56,57). Our report extends these studies by identifying a murine model for roseolovirus infection.…”

Advances in the Characterization of the T-Cell Response to Human Herpesvirus-6

“…Pig tailed macaques ( 88 ), marmosets ( 89 ), cynomolgus macaques, and African green monkeys ( 90 ) are susceptible to human roseolovirus strains and have been used as models in a few studies ( 91 , 92 ). Endogenous roseoloviruses have recently been described in chimpanzees ( 93 ) and rhesus macaques ( 94 ). Once we understand more about the natural history of these infections in their natural hosts and how well they mimic HHV-6 in humans, it may become rational to use them as informative model systems.…”

High Diversity and Novel Enteric Viruses in Fecal Viromes of Healthy Wild and Captive Thai Cynomolgus Macaques (Macaca fascicularis)

“…The same macaque also shed a papillomavirus showing a contig (660 nt) showing best match to gammapapillomavirus 22 (82.5% amino acid identity). Both of these viruses have been associated with oral infections [47,48].…”

“…Another herpesvirus ( Macaca nemestrina herpesvirus 7 or MneHV7) was shed by one animal. MneHV7 is roselovirus in the group of betaherpesvirus infecting salivary gland of macaques [47] and is the viral homolog of human herpesvirus 7 (HHV7) which can be detected in the human oral cavity [47]. The same animal was also infected by a gammapapillomavirus related to oral tissue-infecting gammapapillomavirus 22 or human papillomavirus 172 [48] suggesting MneHV7 and gammapapillomavirus co-infection, possibly in its oral cavity, followed by fecal shedding.…”