Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus

Logsdon, Naomi J.; Eberhardt, Meghan K.; Allen, Colin; Barry, Peter A.; Walter, Mark R.

doi:10.1371/journal.pone.0028127

Cited by 19 publications

(40 citation statements)

References 61 publications

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“…The construction of two nonfunctional forms of rhcmvIL-10, termed rhcmvIL-10M1 and rhcmvIL-10M2, has been described previously (20). The M1 and M2 variants of rhcmvIL-10 each contain two site-directed amino acid changes that prevent the recombinant proteins from (i) binding IL-10R and (ii) suppressing proinflammatory cytokine production by LPS-activated PBMC.…”

Section: Animalsmentioning

confidence: 99%

“…The M1 and M2 variants of rhcmvIL-10 each contain two site-directed amino acid changes that prevent the recombinant proteins from (i) binding IL-10R and (ii) suppressing proinflammatory cytokine production by LPS-activated PBMC. Four RhCMV-uninfected animals were immunized with rhcmvIL-10M1 and -M2 plasmids at week 0, as previously described (23), and subsequently boosted with rhcmvIL-10M1/M2 protein at weeks 6, 12, and 26, as described previously (19,20). In brief, DNA recombinant expression constructs, pND/rhcmvIL-10M1 and pND/rhcmvIL-10M2 (20), were purified using an endotoxin-free plasmid purification kit (Qiagen), and the DNA concentration was determined spectrophotometrically.…”

Section: Animalsmentioning

confidence: 99%

“…DNA was then diluted in phosphate-buffered saline (PBS) buffer at 1 mg/ml and stored at Ϫ80°C. rhcmvIL-10M1 and rhcmvIL-10M2 proteins, expressed from a pMT expression vector system in Drosophila melanogaster S2 cells, were purified by nickel affinity purification protocol as previously described (20). Four RhCMV-negative rhesus macaques were immunized with a combination of rhcmvIL-10M1 and rhcmvIL-10M2 using a heterologous DNA prime-protein boost immunization strategy (23 (23).…”

Section: Animalsmentioning

confidence: 99%

“…In support of this, rhesus macaques inoculated with an RhCMV variant lacking rhcmvIL-10 function exhibit increased inflammatory responses and greater RhCMV-specific antibody and T cell responses than animals inoculated with the parental virus expressing rhcmvIL-10 (18). A mechanistic basis for these observations is suggested by the fact that rhcmvIL-10 suppresses the production of IL-12 in lipopolysaccharide (LPS)-activated peripheral blood mononuclear cells (PBMC) (19,20). Together, these studies highlight HCMV modulation of host immunity and lead to the hypothesis that strategies that prevent HCMV-mediated activation of IL-10R signaling during the earliest stage of primary infection should significantly alter the virus-host relationship to augment host antiviral immunity.…”

mentioning

confidence: 99%

“…Together, these studies highlight HCMV modulation of host immunity and lead to the hypothesis that strategies that prevent HCMV-mediated activation of IL-10R signaling during the earliest stage of primary infection should significantly alter the virus-host relationship to augment host antiviral immunity. To this end, biologically inert forms of rhcmvIL-10 (rhcmvIL-10M1 and rhcmvIL-10M2), which were previously demonstrated to be incapable of both binding to IL-10R and suppressing activation of lymphoid cells (20), were evaluated as vaccine antigens in RhCMV-uninfected rhesus macaques.…”

mentioning

confidence: 99%

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Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Eberhardt

Deshpande

Chang

et al. 2013

J Virol

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T here is ample precedent from studies of licensed viral and microbial vaccines that vaccine-mediated stimulation of pathogen-specific B cell immunity is critical for protection from infection and/or disease (1). Many new vaccine designs are predicated on the induction of antibodies that neutralize viral attachment to susceptible cells. As phase 2 clinical trials on human cytomegalovirus (HCMV) vaccination have shown, however, this approach only partially protects against challenge virus infection. In one study, seronegative women who had given birth within the previous year were vaccinated against HCMV glycoprotein B (gB) (2), the predominant virion target for antibodies that neutralize infection of fibroblasts. While significant protection against primary HCMV infection was observed in the vaccine group, the effect was limited in magnitude (50%) and duration. In the second placebocontrolled, randomized study, liver and kidney transplant candidates were similarly immunized with gB and prospectively evaluated for parameters of HCMV infection posttransplantation (3). Vaccine-mediated increases in gB-specific antibody titers were inversely correlated with the duration of HCMV viremia posttransplantation. Similar to the trial involving seronegative women, however, vaccination against gB alone in transplant recipients did not completely protect those at risk for HCMV infection.

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Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Eberhardt

Deshpande

Chang

et al. 2013

J Virol

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Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines

Boppana

Britt

2021

Methods in Molecular Biology

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Recent Approaches and Strategies in the Generation of Antihuman Cytomegalovirus Vaccines

Boppana

Britt

2014

Methods in Molecular Biology

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The development of prophylactic and to lesser extent therapeutic vaccines for the prevention of disease associated with human cytomegalovirus (HCMV) infections has received considerable attention from biomedical researchers and pharmaceutical companies over the previous 15 years, even though attempts to produce such vaccines have been described in the literature for over 40 years. Studies of the natural history of congenital HCMV infection and infection in allograft recipients have suggested that prophylaxis of disease associated with HCMV infection could be possible, particularly in hosts at risk for more severe disease secondary to the lack of preexisting immunity. Provided a substantial understanding of immune response to HCMV together with several animal models that faithfully recapitulate aspects of human infection and immunity, investigators seem well positioned to design and test candidate vaccines. Yet more recent studies of the role of a maternal immunity in the natural history of congenital HCMV infection, including the recognition that reinfection of previously immune women by genetically distinct strains of HCMV occur in populations with a high seroprevalence, have raised several questions about the nature of protective immunity in maternal populations. This finding coupled with observations that have documented a significant incidence of damaging congenital infections in offspring of women with immunity to HCMV prior to conception has suggested that vaccine development based on conventional paradigms of adaptive immunity to viral infections may be of limited value in the prevention of damaging congenital HCMV infections. Perhaps a more achievable goal will be prophylactic vaccines to modify HCMV associated disease in allograft transplant recipients. Although recent descriptions of the results from vaccine trials have been heralded as evidence of an emerging success in the quest for a HCMV vaccine, careful analyses of these studies have also revealed that major hurdles remain to be addressed by current strategies.

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Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus

Cited by 19 publications

References 61 publications

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Recent Approaches and Strategies in the Generation of Anti-human Cytomegalovirus Vaccines

Recent Approaches and Strategies in the Generation of Antihuman Cytomegalovirus Vaccines

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