scholarly journals Host Immune Responses to a Viral Immune Modulating Protein: Immunogenicity of Viral Interleukin-10 in Rhesus Cytomegalovirus-Infected Rhesus Macaques

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37931 ◽  
Author(s):  
Meghan K. Eberhardt ◽  
W. L. William Chang ◽  
Naomi J. Logsdon ◽  
Yujuan Yue ◽  
Mark R. Walter ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaques ◽  
Interleukin 10 ◽  
Host Immune Responses ◽  
Rhesus Cytomegalovirus

scholarly journals Neutralization of rhesus cytomegalovirus IL-10 reduces horizontal transmission and alters long-term immunity

2019 ◽  
Vol 116 (26) ◽  
pp. 13036-13041 ◽  
Author(s):  
Jesse D. Deere ◽  
W. L. William Chang ◽  
Andradi Villalobos ◽  
Kimberli A. Schmidt ◽  
Ashlesha Deshpande ◽  
...  
Keyword(s):  
Immune Responses ◽  
Persistent Infection ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Horizontal Transmission ◽  
Severe Disease ◽  
Interleukin 10 ◽  
Primate Model ◽  
Host Immune Responses ◽  
Rhesus Cytomegalovirus

Human cytomegalovirus (HCMV) causes severe disease in infants and immunocompromised people. There is no approved HCMV vaccine, and vaccine development strategies are complicated by evidence of both persistent infection and reinfection of people with prior immunity. The greatest emphasis has been placed on reducing transmission to seronegative pregnant women to prevent vertical transmission and its potentially severe sequelae. Increasing evidence suggests that the earliest host–HCMV interactions establish conditions for viral persistence, including evasion of host immune responses to the virus. Using a nonhuman primate model of HCMV infection, we show that rhesus macaques immunized against viral interleukin-10 (IL-10) manifest delayed rhesus cytomegalovirus (RhCMV) acquisition and altered immune responses to the infection when it does occur. Among animals with the greatest antiviral IL-10–neutralizing activity, the timing of RhCMV seroconversion was delayed by an average of 12 weeks. After acquisition, such animals displayed an antibody response to the new infection, which peaked as expected after 2 weeks but then declined rapidly. In contrast, surprisingly, vaccination with glycoprotein B (gB) protein had no discernible impact on these outcomes. Our results demonstrate that viral IL-10 is a key regulator of successful host immune responses to RhCMV. Viral IL-10 is, therefore, an important target for vaccine strategies against cytomegalovirus (CMV). Furthermore, given the immunoregulatory function of viral IL-10, targeting this protein may prove synergistic with other vaccine therapies and targets. Our study also provides additional evidence that the earliest host–CMV interactions can have a significant impact on the nature of persistent infection.

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

2016 ◽  
Vol 90 (21) ◽  
pp. 9920-9930 ◽  
Author(s):  
Meghan K. Eberhardt ◽  
Ashlesha Deshpande ◽  
Joseph Fike ◽  
Rebecca Short ◽  
Kimberli A. Schmidt ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Interleukin 10 ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Rhesus Cytomegalovirus

ABSTRACT 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. IMPORTANCE Human 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-10 signaling pathway.

scholarly journals Immunogenicity and Protective Efficacy of DNA Vaccines Expressing Rhesus Cytomegalovirus Glycoprotein B, Phosphoprotein 65-2, and Viral Interleukin-10 in Rhesus Macaques

2006 ◽  
Vol 81 (3) ◽  
pp. 1095-1109 ◽  
Author(s):  
Yujuan Yue ◽  
Amitinder Kaur ◽  
Meghan K. Eberhardt ◽  
Nadine Kassis ◽  
Shan Shan Zhou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Dna Vaccines ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Interleukin 10 ◽  
Antibody Responses ◽  
Glycoprotein B ◽  
Viral Loads ◽  
Rhesus Cytomegalovirus

ABSTRACT Rhesus cytomegalovirus (RhCMV) infection of macaques exhibits strong similarities to human CMV (HCMV) persistence and pathogenesis. The immunogenicity of DNA vaccines encoding three RhCMV proteins (a truncated version of glycoprotein B lacking the transmembrane region and endodomain [gBΔTM], phosphoprotein 65-2 [pp65-2], and viral interleukin-10 [vIL-10]) was evaluated in rhesus macaques. Two groups of monkeys (four per group) were genetically immunized four times with a mixture of either pp65-2 and gBΔTM or pp65-2, vIL-10, and gBΔTM. The vaccinees developed anti-gB and anti-pp65-2 antibodies in addition to pp65-2 cellular responses after the second booster immunization, with rapid responses observed with subsequent DNA injections. Weak vIL-10 immune responses were detected in two of the four immunized animals. Neutralizing antibodies were detected in seven monkeys, although titers were weak compared to those observed in naturally infected animals. The immunized monkeys and naïve controls were challenged intravenously with 105 PFU of RhCMV. Anamnestic binding and neutralizing antibody responses were observed 1 week postchallenge in the vaccinees. DNA vaccination-induced immune responses significantly decreased peak viral loads in the immunized animals compared to those in the controls. No difference in peak viral loads was observed between the pp65-2/gBΔTM DNA- and pp65-2/vIL-10/gBΔTM-vaccinated groups. Antibody responses to nonvaccine antigens were lower postchallenge in both vaccine groups than in the controls, suggesting long-term control of RhCMV protein expression. These data demonstrated that DNA vaccines targeting the RhCMV homologues of HCMV gB and pp65 altered the course of acute and persistent RhCMV infection in a primate host.

scholarly journals Characterization and immunological analysis of the rhesus cytomegalovirus homologue (Rh112) of the human cytomegalovirus UL83 lower matrix phosphoprotein (pp65)

2006 ◽  
Vol 87 (4) ◽  
pp. 777-787 ◽  
Author(s):  
Yujuan Yue ◽  
Amitinder Kaur ◽  
Shan Shan Zhou ◽  
Peter A. Barry
Keyword(s):  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Rhesus Macaques ◽  
Open Reading Frames ◽  
Cross Sectional ◽  
Host Immune Responses ◽  
Macaque Model ◽  
Cell Responses ◽  
Rhesus Cytomegalovirus ◽  
Humoral Responses

Rhesus cytomegalovirus (RhCMV) contains two open reading frames (Rh111 and Rh112) that encode proteins homologous to the phosphoprotein 65 (pp65) of the human cytomegalovirus (HCMV) UL83 gene. As HCMV pp65 elicits protective immune responses in infected humans and represents an important vaccination target, one RhCMV homologue of HCMV pp65, pp65-2 (Rh112), was characterized and analysed for its ability to induce host immune responses. Similar to its HCMV counterpart, RhCMV pp65-2 was expressed as a late gene, localized to the nucleus within pp65-2-expressing cells and was present within infectious virions. Longitudinal and cross-sectional studies of pp65-2 immunity in naturally infected rhesus macaques showed that humoral responses to pp65-2 were elicited early during infection, but were not always sustained over time. In contrast, pp65-2-specific T-cell responses, examined by gamma interferon ELISPOT, were broadly detectable in all of the animals studied during primary infection and persisted in the vast majority of RhCMV-seropositive monkeys. Moreover, there was considerable inter-animal variability in the pattern of the immune responses to pp65-2. Together, these results demonstrated that RhCMV pp65-2 exhibited biological and immunological homology to HCMV pp65. Thus, the rhesus macaque model of HCMV persistence and pathogenesis should be relevant for addressing pp65-based vaccine modalities.

scholarly journals Genetically barcoded SIV reveals the emergence of escape mutations in multiple viral lineages during immune escape

2019 ◽  
Vol 117 (1) ◽  
pp. 494-502
Author(s):  
Taina T. Immonen ◽  
Celine Camus ◽  
Carolyn Reid ◽  
Christine M. Fennessey ◽  
Gregory Q. Del Prete ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Escape ◽  
Rhesus Macaques ◽  
Quantitative Measure ◽  
Population Level ◽  
Therapeutic Interventions ◽  
Viral Escape ◽  
Virus Population ◽  
Host Immune Responses ◽  
Immune Pressure

The rapidity of replication coupled with a high mutation rate enables HIV to evade selective pressures imposed by host immune responses. Investigating the ability of HIV to escape different selection forces has generally relied on population-level measures, such as the time to detectable escape mutations in plasma and the rate these mutations subsequently take over the virus population. Here we employed a barcoded synthetic swarm of simian immunodeficiency virus (SIV) in rhesus macaques to investigate the generation and selection of escape mutations within individual viral lineages at the Mamu-A*01-restricted Tat-SL8 epitope. We observed the persistence of more than 1,000 different barcode lineages following selection after acquiring escape mutations. Furthermore, the increased resolution into the virus population afforded by barcode analysis revealed changes in the population structure of the viral quasispecies as it adapted to immune pressure. The high frequency of emergence of escape mutations in parallel viral lineages at the Tat-SL8 epitope highlights the challenge posed by viral escape for the development of T cell-based vaccines. Importantly, the level of viral replication required for generating escape mutations in individual lineages can be directly estimated using the barcoded virus, thereby identifying the level of efficacy required for a successful vaccine to limit escape. Overall, assessing the survival of barcoded viral lineages during selection provides a direct and quantitative measure of the stringency of the underlying genetic bottleneck, making it possible to predict the ability of the virus to escape selective forces induced by host immune responses as well as during therapeutic interventions.

scholarly journals Modulation of Host Immune Responses by the Cytolethal Distending Toxin of Helicobacter hepaticus

2006 ◽  
Vol 74 (8) ◽  
pp. 4496-4504 ◽  
Author(s):  
Jason S. Pratt ◽  
Kacey L. Sachen ◽  
Heather D. Wood ◽  
Kathryn A. Eaton ◽  
Vincent B. Young
Keyword(s):  
Immune Responses ◽  
Interleukin 10 ◽  
Cytolethal Distending Toxin ◽  
Helicobacter Hepaticus ◽  
Deficient Mutant ◽  
Wild Type ◽  
Host Immune Responses ◽  
Time Point

ABSTRACT Persistent murine infection with Helicobacter hepaticus leads to chronic gastrointestinal inflammation and neoplasia in susceptible strains. To determine the role of the virulence factor cytolethal distending toxin (CDT) in the pathogenesis of this organism, interleukin-10-deficient (IL-10−/−) mice were experimentally infected with wild-type H. hepaticus and a CDT-deficient isogenic mutant. Both wild-type H. hepaticus and the CDT-deficient mutant successfully colonized IL-10−/− mice, and they reached similar tissue levels by 6 weeks after infection. Only animals infected with wild-type type H. hepaticus developed significant typhlocolitis. However, by 4 months after infection, the CDT-deficient mutant was no longer detectable in IL-10−/− mice, whereas wild-type H. hepaticus persisted for the 8-month duration of the experiment. Animals infected with wild-type H. hepaticus exhibited severe typhlocolitis at 8 months after infection, while animals originally challenged with the CDT-deficient mutant had minimal cecal inflammation at this time point. In follow-up experiments, animals that cleared infection with the CDT-deficient mutant were protected from rechallenge with either mutant or wild-type H. hepaticus. Animals infected with wild-type H. hepaticus developed serum immunoglobulin G1 (IgG1) and IgG2c responses against H. hepaticus, while animals challenged with the CDT-deficient mutant developed significantly lower IgG2c responses and failed to mount IgG1 responses against H. hepaticus. These results suggest that CDT plays a key immunomodulatory role that allows persistence of H. hepaticus and that in IL-10−/− mice this alteration of the host immune response results in the development of colitis.

scholarly journals Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses

2013 ◽  
Vol 87 (18) ◽  
pp. 10273-10282 ◽  
Author(s):  
S. Avdic ◽  
J. Z. Cao ◽  
B. P. McSharry ◽  
L. E. Clancy ◽  
R. Brown ◽  
...  
Keyword(s):  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Interleukin 10 ◽  
Host Immune Responses

scholarly journals Rhesus Macaque CODEX Multiplexed Immunohistochemistry Panel for Studying Immune Responses During Ebola Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Sizun Jiang ◽  
Nilanjan Mukherjee ◽  
Richard S. Bennett ◽  
Han Chen ◽  
James Logue ◽  
...  
Keyword(s):  
Immune Responses ◽  
Ebola Virus ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Cell Types ◽  
Tissue Imaging ◽  
Host Immune Responses ◽  
Spatially Resolved ◽  
Ebov Infection ◽  
Ffpe Tissues

Non-human primate (NHP) animal models are an integral part of the drug research and development process. For some biothreat pathogens, animal model challenge studies may offer the only possibility to evaluate medical countermeasure efficacy. A thorough understanding of host immune responses in such NHP models is therefore vital. However, applying antibody-based immune characterization techniques to NHP models requires extensive reagent development for species compatibility. In the case of studies involving high consequence pathogens, further optimization for use of inactivated samples may be required. Here, we describe the first optimized CO-Detection by indEXing (CODEX) multiplexed tissue imaging antibody panel for deep profiling of spatially resolved single-cell immune responses in rhesus macaques. This 21-marker panel is composed of a set of 18 antibodies that stratify major immune cell types along with a set three Ebola virus (EBOV)-specific antibodies. We validated these two sets of markers using immunohistochemistry and CODEX in fully inactivated Formalin-Fixed Paraffin-Embedded (FFPE) tissues from mock and EBOV challenged macaques respectively and provide an efficient framework for orthogonal validation of multiple antibody clones using CODEX multiplexed tissue imaging. We also provide the antibody clones and oligonucleotide tag sequences as a valuable resource for other researchers to recreate this reagent set for future studies of tissue immune responses to EBOV infection and other diseases.

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