Induction and Evolution of Cytomegalovirus-Specific CD4+ T Cell Clonotypes in Rhesus Macaques

Price, David A.; Bitmansour, Arlene D.; Edgar, John B.; Walker, Joshua M.; Axthelm, Michael K.; Douek, Daniel C.; Picker, Louis J.

doi:10.4049/jimmunol.180.1.269

Cited by 30 publications

(35 citation statements)

References 55 publications

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“…Similar divergent kinetics of CD8 T cells were also described in BALB/c mice (34) as well as in HCMV infection where HCMV-specific CD8 T cell frequencies are highly increased in elderly compared with young individuals (35,36). With respect to CMV-specific CD4 T cell dynamics, data from human as well as rhesus macaque studies also indicated an "inflationary" behavior of CMV-specific CD4 T cells in seropositive individuals during latent stages of infection (37,38).…”

Section: Discussionsupporting

confidence: 52%

The Dynamics of Mouse Cytomegalovirus-Specific CD4 T Cell Responses during Acute and Latent Infection

Walton

Wyrsch

Munks

et al. 2008

The Journal of Immunology

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The dynamics of mouse cytomegalovirus (MCMV)-specific CD4 T cell responses and the mechanisms by which these cells contribute to viral control are not well understood, mainly due to lack of appropriate tools to characterize MCMV-specific CD4 T cells. We therefore generated MCMV-specific CD4 T cell hybridomas, then used an MCMV expression library and overlapping peptides to identify CD4 T cell epitopes. We used these novel tools to study the long-term kinetics and organ distribution of MCMV-specific CD4 T cells in comparison to MCMV-specific CD8 T cell responses. We demonstrate that the overall MCMV-specific CD4 T cell response stabilizes during the latent stage, which stands in contrast to subpopulations of MCMV-specific CD8 T cells and HCMV-specific CD4 T cells which accumulate over the course of CMV latency. Furthermore, MCMV-specific CD4 T cells displayed a Th1 phenotype, secreting high levels of IFN-γ and TNF-α and to some extent IL-2, cytokines which are involved in protection from CMV disease.

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Section: Discussionsupporting

confidence: 52%

The Dynamics of Mouse Cytomegalovirus-Specific CD4 T Cell Responses during Acute and Latent Infection

Walton

Wyrsch

Munks

et al. 2008

The Journal of Immunology

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“…The clonotypic composition of the human pp65-specific CD4 ϩ T-cell repertoire has also been shown to be extremely restricted and stable (23). Similarly, clonal restriction has been noted in the rhesus macaque cytomegalovirus (RhCMV) model (204), whereby the presence of a highly polyclonal RhCMV-specific CD4 ϩ T-cell population during primary infection was followed by a narrowing of the antigen-specific clonotypic repertoire in the chronic phase. Interestingly, challenge with RhCMV instigated the reemergence and dominance of RhCMV-specific CD4 ϩ T-cell clonotypes that were detected only during the acute phase of infection.…”

Section: Ii) Cd4 ؉ T Cells While the Role Of The Major Histocompatibmentioning

confidence: 94%

Immunobiology of Human Cytomegalovirus: from Bench to Bedside

2009

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SUMMARY Following primary infection, human cytomegalovirus (HCMV) establishes lifelong latency and periodically reactivates without causing symptoms in healthy individuals. In the absence of an adequate host-derived immune response, this fine balance of permitting viral reactivation without causing pathogenesis is disrupted, and HCMV can subsequently cause invasive disease and an array of damaging indirect immunological effects. Over the last decade, our knowledge of the immune response to HCMV infection in healthy virus carriers and diseased individuals has allowed us to translate these findings to develop better diagnostic tools and therapeutic strategies. The application of these emerging technologies in the clinical setting is likely to provide opportunities for better management of patients with HCMV-associated diseases.

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“…Our previous studies have noted infrequent and low levels of shedding of 68-1 following either intravenous or subcutaneous inoculation, far below the levels seen in naturally infected monkeys (1,37,78,79). Others have noted relatively high titers of 68-1 in saliva following inoculation of either RhCMV-seronegative or -seropositive macaques, as well as the recovery of virus in urine (33,35,56). The reasons for differences in the quantifications of RhCMV 68-1 genomes in mucosal fluids between different groups is not known and may be related to differences in methodologies.…”

Section: Discussionmentioning

confidence: 99%

Open Reading Frames Carried on UL/b′ Are Implicated in Shedding and Horizontal Transmission of Rhesus Cytomegalovirus in Rhesus Monkeys

Oxford

Strelow

Yue

et al. 2011

J Virol

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Implicit with the use of animal models to test human cytomegalovirus (HCMV) vaccines is the assumption that the viral challenge of vaccinated animals reflects the anticipated virus-host interactions following exposure of vaccinated humans to HCMV. Variables of animal vaccine studies include the route of exposure to and the titer of challenge virus, as well as the genomic coding content of the challenge virus. This study was initiated to provide a better context for conducting vaccine trials with nonhuman primates by determining whether the in vivo phenotype of culture-passaged strains of rhesus cytomegalovirus (RhCMV) is comparable to that of wild-type RhCMV (RhCMV-WT), particularly in relation to the shedding of virus into bodily fluids and the potential for horizontal transmission. Results of this study demonstrate that two strains containing a fulllength UL/b region of the RhCMV genome, which encodes proteins involved in epithelial tropism and immune evasion, were persistently shed in large amounts in bodily fluids and horizontally transmitted, whereas a strain lacking a complete UL/b region was not shed or transmitted to cagemates. Shedding patterns exhibited by strains encoding a complete UL/b region were consistent with patterns observed in naturally infected monkeys, the majority of whom persistently shed high levels of virus in saliva for extended periods of time after seroconversion. Frequent viral shedding contributed to a high rate of infection, with RhCMV-infected monkeys transmitting virus to one naïve animal every 7 weeks after introduction of RhCMV-WT into an uninfected cohort. These results demonstrate that the RhCMV model can be designed to rigorously reflect the challenges facing HCMV vaccine trials, particularly those related to horizontal transmission.Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus with a worldwide seroprevalence of 50 to Ͼ90% in adults (8,14). HCMV elicits a subclinical outcome for the majority of infections in immunocompetent individuals but is a significant pathogen in those without a fully functional immune system. Groups at increased risk for HCMV clinical sequelae include immunologically immature fetuses, immunosuppressed transplant recipients, and immunodeficient AIDS patients. The nearly 4-decade quest for a vaccine that confers protective immunity against HCMV infection has focused primarily on inhibiting primary infection in women without preconceptional immunity to HCMV to prevent transplacental transmission of the virus to the fetus (30). Progress on this front has been reported for a subunit vaccine directed at viral glycoprotein B (gB), which is essential for virus attachment to fibroblasts and is a prominent target of neutralizing antibodies during natural infection (38). A clinical trial with seronegative pregnant women demonstrated that vaccination against gB can reduce primary infection in the vaccine recipients by 50% compared to levels of infection in unvaccinated controls (49). The absence of complete protection in the vaccinees suggests that...

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Induction and Evolution of Cytomegalovirus-Specific CD4+ T Cell Clonotypes in Rhesus Macaques

Cited by 30 publications

References 55 publications

The Dynamics of Mouse Cytomegalovirus-Specific CD4 T Cell Responses during Acute and Latent Infection

The Dynamics of Mouse Cytomegalovirus-Specific CD4 T Cell Responses during Acute and Latent Infection

Immunobiology of Human Cytomegalovirus: from Bench to Bedside

Open Reading Frames Carried on UL/b′ Are Implicated in Shedding and Horizontal Transmission of Rhesus Cytomegalovirus in Rhesus Monkeys

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