Mechanisms modulating immune clearance during human cytomegalovirus latency

Slobedman, Barry; Mocarski, Edward S.

doi:10.1073/pnas.1212245109

Cited by 4 publications

(5 citation statements)

References 25 publications

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“…Results of these studies have suggested that the blood contains a large pool of CMV-specific circulating Tem cells, guarding against potential systemic reactivation, whereas both the site of primary entry (lungs) and extensive initial replication and shedding (salivary gland) contain Trm cells standing guard against potential reinfection (lung) and/or local reactivation (lung and salivary gland). CMV is believed to infect many cells, but to establish latency only in very few [7,60,61]. In that context and in the context of an early and lifelong CMV infection and immunity, we know very little about CMV-specific CD8 T cell immunity and control in other tissues.…”

Section: Discussionmentioning

confidence: 99%

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia

et al. 2019

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Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world’s population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.

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Section: Discussionmentioning

confidence: 99%

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia

et al. 2019

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“…A good model to study antigen‐specific CD4 + memory responses is CMV infection. The beta‐herpes virus CMV replicates systemically after establishing infection via the mucosa, targeting various epithelial, endothelial and myeloid cells, maintaining long‐term residence in precursors of macrophages and dendritic cells 10 . Once these cells become terminally differentiated APCs, they support re‐activation and persistent viral replication and this leads to T‐cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…Healthy individuals mount a broad and sustained antiviral T‐cell response, sometimes up to 10% of total CD4 + and CD8 + T cells can be CMV specific. Despite this extraordinary antiviral response, CMV is never completely cleared, and CMV infection of individuals whose immune system is compromised (such as HIV/AIDS patients) can be life threatening or can cause significant morbidity through reactivation 10 , 11 …”

Section: Discussionmentioning

confidence: 99%

Ratios of effector to central memory antigen‐specific CD4⁺ T cells vary with antigen exposure in HIV+ patients

Phetsouphanh

Bailey

et al. 2014

Immunol Cell Biol

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The OX40/CD25 assay is a novel technique that assesses antigen-specific CD4(+) T-cell responses. To unequivocally demonstrate that responding cells are memory cells that become activated after secondary stimulation, naïve CD45RA(+) and memory CD45RO(+) populations were stimulated with cytomegalovirus (CMV) lysate and the combined expression of CD25 and OX40 measured. As expected, the naïve population showed very little response, whereas there was a higher response from the memory counterpart. To further elucidate CD4(+) memory T-cell subsets involved in recall responses, CD4(+) T cells were separated into central memory (Tcm) and effector memory (Tem) subsets and stimulated with antigen-pulsed antigen-presenting cells (APCs). CMV responses in healthy donors showed a Tem-dominant response with a Tem/Tcm ratio of 1.2, whereas the tetanus toxoid responses were dominated by a Tcm response with a Tem/Tcm ratio of 0.35. To determine memory response in the chronic of HIV infection, patient samples were used. A similar pattern to healthy donors was observed in seven chronic HIV+ patients at week 4 after anti-retroviral therapy who responded to CMV with a larger response coming from Tem. The pattern was similar after 48 weeks of therapy but the responses were lower in magnitude. In chronic HIV+ patients who respond to Gag peptides, following institution of therapy there was an inversion of the ratio of the responding memory subsets compared with week 4, with a greater response from Tcm at week 48. This result was concordant with reduction in antigen load. As immune activation decreased there was also a decrease in the percentage of responding effector memory cells and maintenance of long-term central memory.

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“…The basic mechanisms have been widely investigated and involve complex immunomodulatory processes that ultimately lead to loss of graft function ( 38 – 41 ). In particular, both CMV and EBV contain large DNA genomes that produce various decoy molecules that act at both the intracellular and extracellular levels and interfere with several stages and critical points of immune regulation ( 42 – 45 ). In the present study, several statistical approaches were used to explore the association between CMV and EBV infections and AMR risk among HTxs.…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus and Epstein–Barr virus infections occurring early after transplantation are risk factors for antibody-mediated rejection in heart transplant recipients

Saldan

Mengoli

Sgarabotto³

et al. 2023

Front. Immunol.

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BackgroundAntibody-mediated rejection (AMR) is a serious complication affecting the survival of patients receiving transplantation. Human cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are common viral infections that occur after transplantation, frequently emerging as viral reactivation in donor grafts or transplant recipients. The present study aimed to investigate the association between CMV and EBV infections and early-onset AMR.Materials and methodsThis study was conducted at the Heart Transplantation Center of Padova General Hospital and included a cohort of 47 heart transplant recipients (HTxs), including 24 HTxs diagnosed with AMR and 23 control HTxs with no episodes of AMR. Only early cases of CMV and/or EBV infections (1–90 days after transplantation) were considered. Fisher’s exact test and logistic regression analysis were used to statistically analyze the correlation and association between AMR and CMV or EBV infection.ResultsWe observed a positive statistical association between CMV and EBV infections (two-sided Fisher’s exact test, p = 0.0136) and between EBV infection and AMR (two-sided Fisher’s exact test, p = 0.0034). Logistic regression analysis revealed a direct statistical association between CMV and EBV infections and AMR risk (p = 0.037 and 0.006 and odds ratio = 1.72 and 2.19, respectively). AMR occurrence was associated with increased viral loads of both CMV and EBV early after transplantation.DiscussionThese findings suggest the role of CMV and EBV infections as relevant risk factors for AMR in HTxs for the first time.

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Mechanisms modulating immune clearance during human cytomegalovirus latency

Cited by 4 publications

References 25 publications

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia

Ratios of effector to central memory antigen‐specific CD4⁺ T cells vary with antigen exposure in HIV+ patients

Human cytomegalovirus and Epstein–Barr virus infections occurring early after transplantation are risk factors for antibody-mediated rejection in heart transplant recipients

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Mechanisms modulating immune clearance during human cytomegalovirus latency

Cited by 4 publications

References 25 publications

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia

Ratios of effector to central memory antigen‐specific CD4+ T cells vary with antigen exposure in HIV+ patients

Human cytomegalovirus and Epstein–Barr virus infections occurring early after transplantation are risk factors for antibody-mediated rejection in heart transplant recipients

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Ratios of effector to central memory antigen‐specific CD4⁺ T cells vary with antigen exposure in HIV+ patients