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Cited by 125Cytomegalovirus and herpesvirus researchHerpesvirus Infections and TreatmentsViral-associated cancers and disorders

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Cytomegalovirus viral load within blood increases markedly in healthy people over the age of 70 years

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Parry, Helen M., Zuo, Jianmin, Frumento, Guido, Mirajkar, Nikhil, Inman, Charlotte, Edwards, Emma, Griffiths, Mike, Pratt, Guy, Moss, Paul·2016·Immunity & Ageing
DOI 10.1186/s12979-015-0056-6PMC PMC4700608
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Abstract

BACKGROUND: Cytomegalovirus (CMV) is a highly prevalent herpesvirus, which maintains lifelong latency and places a significant burden on host immunity. Infection is associated with increased rates of vascular disease and overall mortality in the elderly and there is an urgent need for improved understanding of the viral-host balance during ageing. CMV is extremely difficult to detect in healthy donors, however, using droplet digital PCR of DNA from peripheral blood monocytes, we obtained an absolute quantification of viral load in 44 healthy donors across a range of ages. RESULTS: Viral DNA was detected in 24 % (9/37) of donors below the age of 70 but was found in all individuals above this age. Furthermore, the mean CMV load was only 8.6 copies per 10,000 monocytes until approximately 70 years of age when it increased by almost 30 fold to 249 copies in older individuals (p < 0.0001). CMV was found within classical CD14+ monocytes and was not detectable within the CD14-CD16+ subset. The titre of CMV-specific IgG increased inexorably with age indicating that loss of humoral immunity is not a determinant of the increased viral load. In contrast, although cellular immunity to the structural late protein pp65 increased with age, the T cell response to the immediate early protein IE1 decreased in older donors. CONCLUSION: These data reveal that effective control of CMV is impaired during healthy ageing, most probably due to loss of cellular control of early viral reactivation. This information will be of value in guiding efforts to reduce CMV-associated health complications in the elderly.

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Fig. 1 CMV viral load in monocytes increases with ageing. CMV viral load within monocytes increases markedly above the age of 70 years. The DNA of purified CD14+ monocytes was extracted and CMV virus load was detected using droplet digital PCR analysis (ddPCR). a Positive droplets were defined as those detectable above the set threshold as shown in healthy donor (HD) 1 and 3. HD 2 had no detectable CMV viral load. b The CMV virus load was checked in 44 donors, aged between 20 and 90 years of age. The frequency of donors with detectable latent CMV viral load increases with age. c The absolute viral load per 10,000 monocytes was determined by QuantaSoft® software using RRP30 as an internal control. The CMV viral load increases dramatically over the age of 70. d The CMV virus load data was modelled with the exponential growth curve to show the CMV viral load doubling time was 9.6 years
Fig. 1 CMV viral load in monocytes increases with ageing. CMV viral load within monocytes increases markedly above the age of 70 years. The DNA of purified CD14+ monocytes was extracted and CMV virus load was detected using droplet digital PCR analysis (ddPCR). a Positive droplets were defined as those detectable above the set threshold as shown in healthy donor (HD) 1 and 3. HD 2 had no detectable CMV viral load. b The CMV virus load was checked in 44 donors, aged between 20 and 90 years of age. The frequency of donors with detectable latent CMV viral load increases with age. c The absolute viral load per 10,000 monocytes was determined by QuantaSoft® software using RRP30 as an internal control. The CMV viral load increases dramatically over the age of 70. d The CMV virus load data was modelled with the exponential growth curve to show the CMV viral load doubling time was 9.6 yearsCC BY · PubMed Central
Fig. 2 CMV viral load is detectable in CD14 positive monocytes. CMV viral load is detectable within CD34+ haemopoietic cells and is focused within ‘classical’ CD14+ monocytes. DNA from CD34+, CD14 + CD16-, CD14 + CD16+ and CD14-CD16+ populations were used to detect CMV viral load using ddPCR. a Representation of flow plots used for selecting monocyte populations based on CD14+ and CD16+ antibody staining. b Representation of flow plots used for selecting CD34+ cells. c The frequency of detection of CMV viral load was compared between the different subpopulations
Fig. 2 CMV viral load is detectable in CD14 positive monocytes. CMV viral load is detectable within CD34+ haemopoietic cells and is focused within ‘classical’ CD14+ monocytes. DNA from CD34+, CD14 + CD16-, CD14 + CD16+ and CD14-CD16+ populations were used to detect CMV viral load using ddPCR. a Representation of flow plots used for selecting monocyte populations based on CD14+ and CD16+ antibody staining. b Representation of flow plots used for selecting CD34+ cells. c The frequency of detection of CMV viral load was compared between the different subpopulationsCC BY · PubMed Central
Fig. 3 CMV igG titre increases with ageing. CMV-specific IgG antibody titre increased substantially during ageing, with a three-fold increase in titre between the ages of 20 and 80 years
Fig. 3 CMV igG titre increases with ageing. CMV-specific IgG antibody titre increased substantially during ageing, with a three-fold increase in titre between the ages of 20 and 80 yearsCC BY · PubMed Central
Fig. 4 The T cell response to the immunodominant CMV protein pp65 increases with age. T cells were stimulated with peptide pools containing either pp65 or IE-1 and the IFN-g release by peptide-specific CD4 and CD8 T cells was then determined. a Representation of the flow plots for IFN-g response to pp65 and IE-1 peptide stimulation. b Correlation of the T cell response to IE-1 peptides against age demonstrated a peak in people aged 50–60 years followed by a decreased response in older donors. The CD4+ T cell response to IE-1 peptide was small but remained relatively constant across all ages. c Both CD4 and CD8 T cell response to pp65 increase with ageing
Fig. 4 The T cell response to the immunodominant CMV protein pp65 increases with age. T cells were stimulated with peptide pools containing either pp65 or IE-1 and the IFN-g release by peptide-specific CD4 and CD8 T cells was then determined. a Representation of the flow plots for IFN-g response to pp65 and IE-1 peptide stimulation. b Correlation of the T cell response to IE-1 peptides against age demonstrated a peak in people aged 50–60 years followed by a decreased response in older donors. The CD4+ T cell response to IE-1 peptide was small but remained relatively constant across all ages. c Both CD4 and CD8 T cell response to pp65 increase with ageingCC BY · PubMed Central
Fig. 5 An overview of the parallel changes in viral load and immunity during the lifetime of an individual infected with Cytomegalovirus. Schematic representation of the relative changes in the peripheral blood viral load as well as humoral and T cell immune response to CMV over the human life-course. Primary infection is shown as occurring during childhood, the most common age of infection. CMV viral load and CMV-specific IgG antibody titre increases during ageing. CD8 T cell responses to IE-1 peptides peaked in people aged 50–60 years and then decreased in older donors, while T cell response to pp65 peptides increase with ageing
Fig. 5 An overview of the parallel changes in viral load and immunity during the lifetime of an individual infected with Cytomegalovirus. Schematic representation of the relative changes in the peripheral blood viral load as well as humoral and T cell immune response to CMV over the human life-course. Primary infection is shown as occurring during childhood, the most common age of infection. CMV viral load and CMV-specific IgG antibody titre increases during ageing. CD8 T cell responses to IE-1 peptides peaked in people aged 50–60 years and then decreased in older donors, while T cell response to pp65 peptides increase with ageingCC BY · PubMed Central

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Metadata

Authors
Parry, H. M., Zuo, J., Frumento, G., Mirajkar, N., Inman, C., Edwards, E., Griffiths, M., Pratt, G., & Moss, P.
Affiliations
  • University of Birmingham (GB)
  • Birmingham Women's Hospital (GB)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
Corresponding author
Parry, Helen M.
ORCID
Venue
Immunity & Ageing
Publisher
Springer Science and Business Media LLC
Published
2016-01-05
Volume
13
Issue
1
Pages
1-1
ISSN
1742-4933 (ISSN-L)
DOI
10.1186/s12979-015-0056-6
PMC
PMC4700608
OpenAlex
W2222815228
Cited by
125
References
44
Citations by year
2026: 5 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 2 · 2021: 24 · 2020: 14 · 2019: 21 · 2018: 10 · 2017: 19 · 2016: 8
FWCI
18.12
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Immunity & Ageing (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Worcester Research and Publications (University of Worcester) (acceptedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
Funders
Wellcome Trust
Topics
  • Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
  • Health Sciences › Medicine › Infectious Diseases › Herpesvirus Infections and Treatments
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
Keywords
cytomegalovirus, viral load, aging, healthy older adults, peripheral blood monocytes, CD14+ monocytes, viral latency, viral reactivation, pp65, IE1, T cell response, humoral immunity, cell-mediated immunity, herpesvirus

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