Specific pathogen free macaque colonies: a review of principles and recent advances for viral testing and colony management

Yee, JoAnn; Vanderford, Thomas H.; Didier, Elizabeth S.; Gray, Stanton B.; Lewis, Anne D.; Roberts, Jeffrey A.; Taylor, Kerry; Bohm, Rudolf P.

doi:10.1111/jmp.12209

Cited by 32 publications

(52 citation statements)

References 93 publications

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“…While intermittent reactivation and shedding of B virus in some animals has been documented (56), its impact on host immunity has not been fully characterized. All non-SPF animals in our study were seronegative for SIV and SRV (51).…”

Section: Discussionmentioning

confidence: 99%

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Rocha

Hirao

Weber

et al. 2018

J Virol

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Subclinical viral infections (SVI), including cytomegalovirus (CMV), are highly prevalent in humans, resulting in lifelong persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (specific-pathogen-free [SPF]) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function, as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producing Firmicutes and higher numbers of lymphocytes, effector T cells, and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level. IMPORTANCE Humans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines, and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immunocompromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Rocha

Hirao

Weber

et al. 2018

J Virol

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“…NWP SFV WB-positive individuals had an overall shorter duration of NWP exposure compared with seronegative workers, though some SFV-positive workers were consistently seroreactive and had decades of exposure. Although this is the first evidence of antibody clearance in SFV infection, other retroviruses, such as simian type D retrovirus (SRV), can present as latent infections with the presence of integrated virus detected by PCR and/or tissue culture but without antibody detection and with each SRV analyte waxing and waning overtime without consistent detection [ 42 ]. Antibody clearance could also reflect possible abortive infections.…”

Section: Discussionmentioning

confidence: 99%

Zoonotic infection of Brazilian primate workers with New World simian foamy virus

et al. 2017

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Simian foamy viruses (SFVs) are retroviruses present in nearly all nonhuman primates (NHPs), including Old World primates (OWP) and New World primates (NWP). While all confirmed human infections with SFV are from zoonotic transmissions originating from OWP, little is known about the zoonotic transmission potential of NWP SFV. We conducted a longitudinal, prospective study of 56 workers occupationally exposed to NWP in Brazil. Plasma from these workers was tested using Western blot (WB) assays containing NWP SFV antigens. Genomic DNA from blood and buccal swabs was analyzed for the presence of proviral SFV sequences by three nested PCR tests and a new quantitative PCR assay. Exposure histories were obtained and analyzed for associations with possible SFV infection. Ten persons (18%) tested seropositive and two persons were seroindeterminate (3.6%) for NWP SFV. Six persons had seroreactivity over 2–3 years suggestive of persistent infection. All SFV NWP WB-positive workers reported at least one incident involving NWP, including six reporting NWP bites. NWP SFV viral DNA was not detected in the blood or buccal swabs from all 12 NWP SFV seroreactive workers. We also found evidence of SFV seroreversion in three workers suggestive of possible clearance of infection. Our findings suggest that NWP SFV can be transmitted to occupationally-exposed humans and can elicit specific humoral immune responses but infection remains well-controlled resulting in latent infection and may occasionally clear.

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“…The prevention of human exposure to BV, specific detection of BV infection of humans and establishment of BV-free macaque colonies (Yee et al, 2016) depend on the availability of diagnostic systems, which allow for the detection of antibodies against simplex viruses of human and NHP origin with high sensitivity and specificity. Our study shows that SA8-and HPV-2-infected cells allow for the detection of antibodies raised against BV with higher sensitivity than HSV-1-and HSV-2-infected cells.…”

Section: Discussionmentioning

confidence: 99%

Detection systems for antibody responses against herpes B virus

et al. 2017

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Abstract. Herpes B virus (BV) infection is highly prevalent among adult Asian macaques and rarely causes severe disease in infected animals. In contrast, BV infection of humans can induce fatal encephalitis in the absence of treatment. Therefore, the development of diagnostic tests for specific and sensitive detection of antibodies against BV is an important task. The cross-reactivity of antibodies against BV with related simplex viruses of other primates may afford an opportunity to obtain sensitive detection systems without the need to work with the highly pathogenic BV. Moreover, it has been proposed that use of recombinant viral glycoproteins may allow for a detection of antibody responses against BV with high specificity. However, limited data are available for both approaches to BV diagnostic. Here, we report that simian agent 8 (SA8; infects African green monkeys)-and herpesvirus papio 2 (HVP-2; infects baboons)-infected cells allow for a more sensitive detection of antibody responses against BV in macaques than lysates of herpes simplex virus type 1 and 2 (HSV-1/2; infect humans)-infected cells and a commercial HSV ELISA (Enzygnost ® Anti-HSV/IgG). In addition, we show that sera from BV-infected macaques frequently contain antibodies against the recombinant BV glycoprotein gD (BV gD) that has been previously proposed as a diagnostic target for discriminating BV-and HSV-induced antibodies. However, we found that antibodies of some HSV-infected human patients also reacted with BV gD. In contrast, only sera of HSV-1-and HSV-2-infected humans, but not sera from BV-infected macaques, reacted with HSV-1/2 gG. Collectively, these results suggest that both SA8 and HVP-2 allow for sensitive and comparable detection of BVdirected antibody responses in macaques and that the combination of BV gD and HSV-1/2 gG needs to be complemented by a least one additional viral glycoprotein for reliable discrimination between antibody responses against BV and HSV-1/2 in humans.

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Specific pathogen free macaque colonies: a review of principles and recent advances for viral testing and colony management

Cited by 32 publications

References 93 publications

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Zoonotic infection of Brazilian primate workers with New World simian foamy virus

Detection systems for antibody responses against herpes B virus

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Specific pathogen free macaque colonies: a review of principles and recent advances for viral testing and colony management

Cited by 32 publications

References 93 publications

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses

Zoonotic infection of Brazilian primate workers with New World simian foamy virus

Detection systems for antibody responses against herpes&#160;B virus

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Product

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Detection systems for antibody responses against herpes B virus