‘Checks and balances’ in cytomegalovirus-host cohabitation

Reddehase, Matthias J.

doi:10.1007/s00430-019-00618-5

Cited by 5 publications

(5 citation statements)

References 8 publications

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“…However, regardless of the initial dose of infection, which is probably always very low in humans, subsequent virus spread in the host that largely depends on the immune status at the time of infection and which is high in the immunologically immature or immunocompromised host, is likely even more important for establishing a high latent viral genome load favoring MI [ 72 , 112 ]. Dependence on the individual infection history, defining the magnitude of productive infection and thus also the latent viral DNA load, explains why MI is not consistently observed in humans ([ 113 ], for a commentary, see [ 114 ]).…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Holtappels,

Becker,

Hamdan

et al. 2023

PLoS Pathog

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Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as “latency”. During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplantation (HCT) recipients in a “window of risk” between therapeutic hemato-ablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM increase in numbers over time in the latently infected host, a phenomenon known as ‘memory inflation’ (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which relies almost entirely on superior proliferative potential of TCM.

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Section: Discussionmentioning

confidence: 99%

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Holtappels,

Becker,

Hamdan

et al. 2023

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, regardless of the initial dose of infection, which is probably always very low in humans, subsequent virus spread in the host that largely depends on the immune status at the time of infection and which is high in the immunologically immature or immunocompromised host, is likely even more important to establish a high latent viral genome load favoring MI [100,102]. Dependence on the individual infection history, defining the magnitude of productive infection and thus also the latent viral DNA load, explains why MI is not consistently observed in humans ([103], for a commentary, see [104]). The human counterpart of iTEM, that is, the cells expanding during MI and thus defining MI, show an ‘advanced differentiation phenotype’ that also includes high expression of KLRG1 and low expression of CD62L [105].…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Holtappels,

Becker,

Hamdan

et al. 2023

Preprint

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Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as ’latency’. During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplantation (HCT) recipients in a “window of risk” between therapeutic hematoablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM, increase in numbers over time in the latently infected host, a phenomenon known as ‘memory inflation’ (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which rests almost exclusively on a superior proliferation potential of TCM.

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“…Memory inflation, characterised by an expansion of the memory T‐cell pool over time, is a hallmark of CMV infection, especially shown in CMV mouse models 23,45,46 . Memory inflation of CMV‐specific T cells in humans was questioned recently 47 .…”

Section: Discussionmentioning

confidence: 99%

“…This may lead to a larger viral reservoir in the elderly and consequently to a larger immune response to enable control of the virus in its latent phase, regardless of duration of CMV infection. Other factors that could influence this balance include the route of viral transmission, 57 the amount of viral inoculum during primary infection, 23 or the state of the immune system at primary infection 45,58 . A comparable model was previously proposed based on data from children, which suggested that the relatively immature state of the immune system in children leads to the establishment of a larger viral reservoir, 45,58 which may subsequently increase the chance of viral reactivation.…”

Section: Discussionmentioning

confidence: 99%

Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27‐year‐long longitudinal study

et al. 2020

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Objectives Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV‐specific antibody levels in the elderly are generally assumed to reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV‐specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation. Methods We studied CMV‐specific antibody levels over ~ 27 years in 268 individuals (aged 60–89 years at study endpoint), and to link duration of CMV infection to T‐cell numbers, CMV‐specific T‐cell functions, frailty and cardiovascular disease at study endpoint. Results In our study, 136/268 individuals were long‐term CMV seropositive and 19 seroconverted during follow‐up (seroconversion rate: 0.56%/year). CMV‐specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV‐specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T‐cell pool was observed. Elevated CMV‐specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV‐specific antibody levels, memory CD4 + T‐cell numbers and frailty. Conclusion Cytomegalovirus‐specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age‐related effects other than duration of CMV infection seem to contribute to CMV‐induced changes in the immune system. Although CMV‐specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.

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‘Checks and balances’ in cytomegalovirus-host cohabitation

Cited by 5 publications

References 8 publications

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Limited effect of duration of CMV infection on adaptive immunity and frailty: insights from a 27‐year‐long longitudinal study

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