Murine Model of Cytomegalovirus Latency and Reactivation

Reddehase, Matthias J.; Simon, Christian O.; Seckert, Christof K.; Lemmermann, Niels A. W.; Grzimek, Natascha K. A.

doi:10.1007/978-3-540-77349-8_18

Cited by 102 publications

(104 citation statements)

References 47 publications

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“…The interference between CD8 T cell responses may be more complex in the HCMV infection of humans because more Ags are expressed and more antigenic epitopes compete for binding/presentation of different MHC class I and II molecules (73). Moreover, persistent viral infections and reactivations may critically affect the longevity of antiviral CD8 T cell responses (50,74,75). In preliminary experiments, we have evaluated the repertoire of pp65-specific CD8 T cell responses in four HCMVseropositive HLA-A*0201 + volunteers.…”

Section: Discussionmentioning

confidence: 99%

The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

Reiser

Wieland

Plachter

et al. 2011

The Journal of Immunology

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Immunodominance hierarchies operating in immune responses to viral Ags limit the diversity of the elicited CD8 T cell responses. We evaluated in I-Ab+/A2-HHD-II and HLA-DR1+/A2-DR1 mice the HLA-A*0201–restricted, multispecific CD8 T cell responses to the human CMV tegument phosphoprotein pp65 (pp65) Ag. Vaccination of mice with pp65-encoding DNA elicited high IFN-γ+ CD8 T cell frequencies to the pp65495–503/(e6) epitope and low responses to the pp65320–328/(e3) and pp65522–530/(e8) epitopes. Abrogation of the e6-specific immunity efficiently enhanced e3- and e8-specific T cell responses by a pp65Δ501–503 DNA vaccine. The immunodominant e6-specific (but not the e3- and e8-specific) CD8 T cell response critically depends on CD4 T cell help. Injection of monospecific DNA- or peptide-based vaccines encoding the e3 or e8 (but not the e6) epitope into mice elicited CD8 T cells. Codelivering the antigenic peptides with different heterologous CD4 T cell helper epitopes enhanced e6-specific (but not e3- or e8-specific) CD8 T cell responses. Similarly, homologous CD4 T cell help, located within an overlapping (nested) pp65487–503 domain, facilitated induction of e6-specific CD8 T cell responses by peptide-based vaccination. The position of the e6 epitope within this nested domain is not critical to induce the immunodominant, e6-specific CD8 T cell response to the pp65 Ag. Distant CD4 T cell epitope(s) can thus provide efficient help for establishing pp65-e6 immunodominance in vaccinated mice. These results have practical implications for the design of new T cell-stimulating vaccines.

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Section: Discussionmentioning

confidence: 99%

The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

Reiser

Wieland

Plachter

et al. 2011

The Journal of Immunology

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“…Because of host species specificity of CMVs, HCMV infection cannot be studied in an animal model. Because MCMV and HCMV share many biological properties and display similarity in pathogenesis, MCMV has become the immunologically best characterized model for the study of CMV infection (17). In the case of MCMV, latent infection is well documented to induce a so-called "memory inflation" of CD8 + T cells recognizing dominant viral peptides and to cause accelerated immunosenescence (18,19).…”

mentioning

confidence: 99%

“…In this work, we studied NK cells 90 to 120 d after MCMV infection when MCMV latency is fully established (17). In this context, an important question was whether residual latent viral gene expression may be sufficient for ongoing NK cell activation.…”

mentioning

confidence: 99%

Genetic Labeling Reveals Altered Turnover and Stability of Innate Lymphocytes in Latent Mouse Cytomegalovirus Infection

Busche

Schmitz

Fleige

et al. 2011

The Journal of Immunology

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Mouse CMV (MCMV) infection rapidly induces the proliferation of NK cells, which correlates with immunological protection. Whether NK cells primed during acute response against MCMV are maintained for the long term is not known. In this study, we used TcrdH2BeGFP mice in which maturing NK cells are genetically labeled with a pulse of very stable histone-2B–eGFP. In this system, we found that the reporter protein was diluted out upon NK cell division during acute MCMV infection. At the same time, mature NK cells in uninfected mice showed only very limited turnover in vivo. Three months after primary infection when MCMV latency was established, the majority of peripheral NK cells still displayed a higher record of proliferation than NK cells in mock-infected controls. This observation included both Ly49H+ and Ly49H– NK cells. Conversely, naive NK cells did not show more proliferation after transfer into latently MCMV-infected mice than that after transfer into mock-infected control mice. This indicated that the observed alterations of the NK cell compartment in MCMV latency were “legacy” (i.e., resulting from prior events during the initial immune response). Together, these results suggest that antiviral immune responses induce sustained alterations of innate lymphocyte populations that extend far beyond the first days of acute infection.

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“…It has been proposed that the Binflationary^CD8 + T cells are involved in the immune surveillance of viral latency by sensing and terminating episodes of viral transcriptional reactivation (Reddehase et al 2008) and that latent gene expression results in the presentation of antigenic peptides that stimulate virus-specific CD8 T cells (Seckert et al 2012). This implies transcription of epitope-encoding viral genes (Aiello et al 2008), translation of these transcripts to the respective antigenic proteins (Borza and Hutt-Fletcher 2002), and efficient antigen processing and epitope presentation (Britt 2008), all of which represent bottlenecks for MI to occur.…”

Section: T Cell Bmemory Inflation^as a Results Of Latency-associated Gmentioning

confidence: 99%

Recent advances in CMV tropism, latency, and diagnosis during aging

et al. 2017

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Human cytomegalovirus (CMV) is one of the largest viruses known to cause human diseases. Chronic CMV infection, as defined by anti-CMV IgG serology, increases with age and is highly prevalent in older adults. It has complex biology with significant immunologic and health consequences. This article aims to summarize research findings presented at the 6th International Workshop on CMV and Immunosenescence that relate to advances in the areas of CMV tropism, latency, CMV manipulation of cell metabolism, and T cell memory inflation, as well as novel diagnostic evaluation and translational research of chronic CMV infection in older adults. Information summarized here represents the current state of knowledge in these important fields. Investigators have also identified a number of areas that deserve further and more in-depth investigation, including building more precise parallels between mouse CMV (mCMV) and human CMV (HCMV) research. It is hoped that this article will also stimulate engaging discussion on strategies and direction to advance the science to the next level.

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Murine Model of Cytomegalovirus Latency and Reactivation

Cited by 102 publications

References 47 publications

The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

Genetic Labeling Reveals Altered Turnover and Stability of Innate Lymphocytes in Latent Mouse Cytomegalovirus Infection

Recent advances in CMV tropism, latency, and diagnosis during aging

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