The Contribution of Cytomegalovirus Infection to Immune Senescence Is Set by the Infectious Dose

Redeker, Anke; Remmerswaal, Ester B. M.; Gracht, Esmé van der; Welten, Suzanne P. M.; Höllt, Thomas; Koning, Frits; Čičin-Šain, Luka; Nikolich‐Žugich, Janko; Berge, Ineke J. M. ten; Lier, René A. W. van; Unen, Vincent van; Arens, Ramon

doi:10.3389/fimmu.2017.01953

Cited by 53 publications

(56 citation statements)

References 50 publications

(64 reference statements)

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“…But this population is on average significantly larger in CKD patients and may comprise over 50% of all circulating CD4 T cells [47]. Remarkably not all CMV seropositive individuals have such an expansion of CD4CD28 negative T cells, which is likely related to the initial infectious dose and the number of CMV reactivations [51,[59][60][61][62]. The total number of CD8 T cells is less affected by ageing, as the decline in naïve CD8 T cells is compensated by an expansion of highly differentiated memory T cells.…”

Section: Renal Failure and Adaptive Immunitymentioning

confidence: 99%

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

Betjes

2020

Toxins

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Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the T cell part of the adaptive immune system is highlighted. Naïve T cell lymphopenia, in combination with the expansion of highly differentiated memory T cells, are the hallmarks of immunological ageing. The decreased production of newly formed T cells by the thymus is critically involved. This affects both the CD4 and CD8 T cell compartment and may contribute to the expansion of memory T cells. The expanding populations of memory T cells have a pro-inflammatory phenotype, add to low-grade inflammation already present in ESRD patients and destabilize atherosclerotic plaques. The effect of loss of renal function on the thymus is not reversed after restoring renal function by kidney transplantation and constitutes a long-term mortality risk factor. Promising results from animal experiments have shown that rejuvenation of the thymus is a possibility, although not yet applicable in humans.

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Section: Renal Failure and Adaptive Immunitymentioning

confidence: 99%

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

Betjes

2020

Toxins

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“…We and others have observed that mice infected with varying doses of mCMV develop variable mCMV‐specific antibody responses . Given the variability in tissue viral loads, we hypothesized that viral antibody responses might be used as a surrogate of underlying tissue viral loads.…”

Section: Resultsmentioning

confidence: 99%

“…We and others have observed that mice infected with varying doses of mCMV develop variable mCMV-specific antibody responses. [11][12][13] Given the variability in tissue viral loads, we hypothesized that viral antibody responses might be used as a surrogate of underlying tissue viral loads. To test this, we compared viral DNA from lungs and mCMV-specific IgG in sera from mice 16 weeks after infection with varying doses of mCMV (10 1 -10 6 pfu).…”

Section: Correlation Of Viral Loads and Igg Responses After Laboratmentioning

confidence: 99%

“…Such tissue‐based studies are lacking, likely because the determination of tissue viral load requires invasive biopsies. Recent work has suggested that differing infectious titers induce different tissue viral loads and correspondingly proportional immune responses . This led us to hypothesize that serum IgG, which seems proportional to the magnitude of primary infection and ensuing tissue viral load, might be useful in predicting those patients with higher tissue viral loads and thus at greatest risk of reactivation.…”

Section: Introductionmentioning

confidence: 99%

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Cytomegalovirus immunoglobulin G titers do not predict reactivation risk in immunocompetent hosts

Mansfield

Dwivedi

Elgharably

et al. 2019

Journal of Medical Virology

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Cytomegalovirus (CMV) reactivation occurs in roughly one‐third of immunocompetent patients during critical illness, and is associated with worse outcomes. These outcomes have prompted consideration of early antiviral prophylaxis, but two‐third of patients would receive unnecessary treatment. Tissue viral load has been associated with risk of reactivation in murine models, and recent work has suggested a relationship between immune responses to CMV and underlying viral load. We, therefore, sought to confirm the hypothesis that serum CMV‐specific immunoglobulin G (IgG) correlates with tissue viral load, and might be used to predict the risk of reactivation during critical illness. We confirm that there is a good correlation between tissue viral load and serum CMV‐specific IgG after laboratory infection of inbred mice. Further, we show that naturally infected outbred hosts have variable tissue viral DNA loads that do not correlate well with serum IgG. Perhaps as a consequence, CMV‐specific IgG was not predictive of reactivation events in immunocompetent humans. When reactivation did occur, those with the lowest IgG levels had longer durations of reactivation, but IgG quartiles were not associated with differing peak DNAemia. Together our data suggest that CMV‐specific IgG titers diverge from tissue viral loads in outbred immunocompetent hosts, and their importance for the control of reactivation events remains unclear.

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“…Whether this relationship is advantageous or detrimental to the immunocompetent host is debatable. On one hand, latent MCMV infection may compromise immune function in aging hosts according to some [76] but not all studies [77]. On the other, MCMV latency could have a beneficial effect on the immune response against bacterial pathogens [78].…”

Section: Mouse-adapted Zebov Ip Challengementioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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The Contribution of Cytomegalovirus Infection to Immune Senescence Is Set by the Infectious Dose

Cited by 53 publications

References 50 publications

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

Cytomegalovirus immunoglobulin G titers do not predict reactivation risk in immunocompetent hosts

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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