The interplay between immune maturation, age, chronic viral infection and environment

Oxford, Kristie; Pena-Ponce, M.G.A. dela; Jensen, Kara; Eberhardt, Meghan K.; Spinner, Abigail; Rompay, Koen K. A. Van; Rigdon, Joseph; Mollan, Katie R.; Krishnan, Viswanathan V; Hudgens, Michael G.; Barry, Peter A.; Paris, Kristina De

doi:10.1186/s12979-015-0030-3

Cited by 35 publications

(53 citation statements)

References 50 publications

(51 reference statements)

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“…Consistent with previous studies, the preponderance of animals exhibited detectable RhCMV DNA in the majority of samples collected (Table 1; see also Fig. 2, below) (20,31). Two animals (MMUs 2 and 3) were positive for RhCMV DNA in 14 of the 16 samples (88%), and 15 animals were positive for every oral swab.…”

Section: Longitudinal Assessment Of Rhcmv Sheddingsupporting

confidence: 73%

“…Blood and saliva were collected from anesthetized animals according to our published protocols (20). RhCMV viral DNA was extracted from plasma and via oral swabs using the QiaSymphony system (Qiagen) according to our published protocols (21).…”

Section: Methodsmentioning

confidence: 99%

“…Once infected with RhCMV, healthy long-term carriers of RhCMV can repeatedly shed virus in bodily fluids (e.g., saliva and urine) for Ͼ20 years (20,30,31). The cross-sectional frequency of RhCMV in bodily fluids declines as animals age.…”

Section: Longitudinal Assessment Of Rhcmv Sheddingmentioning

confidence: 99%

“…The cross-sectional frequency of RhCMV in bodily fluids declines as animals age. Whereas ϳ75% of adolescent to young adult macaques (3 to 5 years) have detectable RhCMV DNA in saliva and/or urine, 25% of older adults (12 to 20 years) are positive for RhCMV DNA in the same bodily fluids (20).…”

Section: Longitudinal Assessment Of Rhcmv Sheddingmentioning

confidence: 99%

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Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Eberhardt

Deshpande

Fike

et al. 2016

J Virol

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There is accumulating evidence that the viral interleukin-10 (vIL-10) ortholog of both human and rhesus cytomegalovirus (HCMV and RhCMV, respectively) suppresses the functionality of cell types that are critical to contain virus dissemination and help shape long-term immunity during the earliest virus-host interactions. In particular, exposure of macrophages, peripheral blood mononuclear cells, monocyte-derived dendritic cells, and plasmacytoid dendritic cells to vIL-10 suppresses multiple effector functions including, notably, those that link innate and adaptive immune responses. Further, vaccination of RhCMV-uninfected rhesus macaques with nonfunctional forms of RhCMV vIL-10 greatly restricted parameters of RhCMV infection following RhCMV challenge of the vaccinees. Vaccinees exhibited significantly reduced shedding of RhCMV in saliva and urine following RhCMV challenge compared to shedding in unvaccinated controls. Based on the evidence that vIL-10 is critical during acute infection, the role of vIL-10 during persistent infection was analyzed in rhesus macaques infected long term with RhCMV to determine whether postinfection vaccination against vIL-10 could change the virus-host balance. RhCMV-seropositive macaques, which shed RhCMV in saliva, were vaccinated with nonfunctional RhCMV vIL-10, and shedding levels of RhCMV in saliva were evaluated. Following robust increases in vIL-10-binding and vIL-10-neutralizing antibodies, shedding levels of RhCMV modestly declined, consistent with the interpretation that vIL-10 may play a functional role during persistent infection. However, a more significant association was observed between the levels of cellular IL-10 secreted in peripheral blood mononuclear cells exposed to RhCMV antigens and shedding of RhCMV in saliva. This result implies that RhCMV persistence is associated with the induction of cellular IL-10 receptor-mediated signaling pathways. IMPORTANCEHuman health is adversely impacted by viruses that establish lifelong infections that are often accompanied with increased morbidity and mortality (e.g., infections with HIV, hepatitis C virus, or human cytomegalovirus). A longstanding but unfulfilled goal has been to develop postinfection vaccine strategies that could "reboot" the immune system of an infected individual in ways that would enable the infected host to develop immune responses that clear reservoirs of persistent virus infection, effectively curing the host of infection. This concept was evaluated in rhesus macaques infected long term with rhesus cytomegalovirus by repeatedly immunizing infected animals with nonfunctional versions of the rhesus cytomegalovirus-encoded viral interleukin-10 immune-modulating protein. Following vaccine-mediated boosting of antibody titers to viral interleukin-10, there was modest evidence for increased immunological control of the virus following vaccination. More significantly, data were also obtained that indicated that rhesus cytomegalovirus is able to persist due to upregulation of the cellular interleukin-...

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Section: Longitudinal Assessment Of Rhcmv Sheddingsupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Longitudinal Assessment Of Rhcmv Sheddingmentioning

confidence: 99%

Section: Longitudinal Assessment Of Rhcmv Sheddingmentioning

confidence: 99%

See 2 more Smart Citations

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Eberhardt

Deshpande

Fike

et al. 2016

J Virol

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“…6A). Thus, it was important to distinguish between changes in peripheral blood immune cell populations that reflect normal postnatal immune development (38) and vaccine-induced immune activation. Therefore, we report all changes in activated CD4 ϩ T cell frequencies as ratios of week 9 values compared to week 0 values for each animal.…”

Section: Resultsmentioning

confidence: 99%

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

Jensen

Pena-Ponce

Piatak

et al. 2017

Clin Vaccine Immunol

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Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4 ϩ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants.

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The relationship of maternal rank, 5‐HTTLPR genotype, and MAOA‐LPR genotype to temperament in infant rhesus monkeys (Macaca mulatta)

Capitanio

Sommet

Rosso

2022

American J Primatol

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Temperament is a construct whose manifestations are quantifiable from an early age, and whose origins have been proposed as "biological." Our goal was to determine whether maternal rank and infant genotype are associated with five measures of temperament in 3-to 4-month old rhesus monkeys (Macaca mulatta), all of whom were born and reared by their mothers in large, outdoor, half-acre cages.Maternal rank was defined as the proportion of animals outranked by each female, and the two genes of interest to us were monoamine oxidase and serotonin transporter, both of which are polymorphic in their promoter regions (MAOA-LPR and 5-HTTLPR, respectively), with one allele of each gene considered a "plasticity" allele, conferring increased sensitivity to environmental events. Our large sample size (n = 2014-3140) enabled us to examine the effects of individual genotypes rather than combining genotypes as is often done. Rank was positively associated with Confident temperament, but only for animals with the 5-repeat allele for MAOA-LPR. Rank had no other effect on temperament. In contrast, genotype had many different effects, with 5-HTTLPR associated with behavioral inhibition, and MAOA-LPR associated with ratings-based measures of temperament. We also examined the joint effect of the two genotypes and found some evidence for a doseresponse: animals with the plasticity alleles for both genes were more likely to be behaviorally inhibited. Our results suggest phenotypic differences between animals possessing alleles for MAOA-LPR that show functional equivalence based on in vitro tests, and our data for 5-HTTLPR revealed differences between short/short homozygotes and long/short heterozygotes, strongly suggesting that combining genotypes for statistical analysis should be avoided if possible. Our analysis also provides evidence of sex differences in temperament, and, to our knowledge, the

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The interplay between immune maturation, age, chronic viral infection and environment

Cited by 35 publications

References 50 publications

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

The relationship of maternal rank, 5‐HTTLPR genotype, and MAOA‐LPR genotype to temperament in infant rhesus monkeys (Macaca mulatta)

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