Proximity of Cytomegalovirus-Specific CD8+ T Cells to Replicative Senescence in Human Immunodeficiency Virus-Infected Individuals

Heath, John J.; Fudge, Neva J.; Gallant, Maureen; Grant, Michael D.

doi:10.3389/fimmu.2018.00201

Cited by 11 publications

(16 citation statements)

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“…HeLa cells are a high telomere content control, and telomere length of HeLa cells was controlled by freshly thawing aliquots from the same passage number on the day of each experiment. After fixation, cells were resuspended in 250 µL PBS with 1% FBS and treated with chemical cross-linker bissulfosuccinimidyl suberate at a final concentration of 5 mM on ice for 30 minutes per a previously published protocol ( 29 ). The reaction was quenched with a 20-minute incubation in quenching solution (PBS with 100 mM Tris-HCl, 50 mM NaCl).…”

Section: Methodsmentioning

confidence: 99%

Association of Premature Immune Aging and Cytomegalovirus After Solid Organ Transplant

Higdon

Gustafson

et al. 2021

Front. Immunol.

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Immune function is altered with increasing age. Infection with cytomegalovirus (CMV) accelerates age-related immunological changes resulting in expanded oligoclonal memory CD8 T cell populations with impaired proliferation, signaling, and cytokine production. As a consequence, elderly CMV seropositive (CMV+) individuals have increased mortality and impaired responses to other infections in comparison to seronegative (CMV–) individuals of the same age. CMV is also a significant complication after organ transplantation, and recent studies have shown that CMV-associated expansion of memory T cells is accelerated after transplantation. Thus, we investigated whether immune aging is accelerated post-transplant, using a combination of telomere length, flow cytometry phenotyping, and single cell RNA sequencing. Telomere length decreased slightly in the first year after transplantation in a subset of both CMV+ and CMV– recipients with a strong concordance between CD57+ cells and short telomeres. Phenotypically aged cells increased post-transplant specifically in CMV+ recipients, and clonally expanded T cells were enriched for terminally differentiated cells post-transplant. Overall, these findings demonstrate a pattern of accelerated aging of the CD8 T cell compartment in CMV+ transplant recipients.

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Section: Methodsmentioning

confidence: 99%

Association of Premature Immune Aging and Cytomegalovirus After Solid Organ Transplant

Higdon

Gustafson

et al. 2021

Front. Immunol.

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“…A recent study found coinfection with CMV was clearly associated with immunosenescence, but not with inflammation in PLWH [96]. Most studies have found an association between coinfection with CMV and increased inflammation [70,[97][98][99] and a large study reported increased risk for non-AIDS related clinical events with CMV coinfection [100].…”

Section: Hiv-associated "Premature" Aging and CMV Co-infectionmentioning

confidence: 99%

“…Expression of similar traits to those observed in senescent fibroblasts by Hayflick et al suggests that CMV-specific T cells could be a peri-senescent immune cell subset. A study of lymphocyte telomere length in HIV-infected individuals positioned CMV-specific CD8 + T cells as having the shortest telomeres and highest rate of telomere attrition [70]. Therefore, the accumulation of such immune cells through extensive proliferation could underlie a relationship between CMV infection and age-associated morbidity.…”

Section: Cytomegalovirus Infection Generates a Unique Cd8 + T-cell Sumentioning

confidence: 99%

“…Although CMV infection is associated with increased numbers of circulating CD8 + T EMRA , it was not taken into consideration for these studies. However, a subsequent study identified CMV-specific CD8 + T cells as having the shortest telomeres and undergoing the most rapid telomere erosion in PLWH [70]. Leukocyte telomere length is also associated with duration of untreated HIV disease and lower CD4 + T cell nadirs [109].…”

Section: Hiv-associated "Premature" Aging and CMV Co-infectionmentioning

confidence: 99%

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The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence

Heath

Grant

2020

Cells

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Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.

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“…Valid data on the effect of CMV infection on CRP levels are scarce. The available evidence shows an effect of CMV infection on CRP levels in HIV-negative patients and HIV-positive individuals with and without ART [ 35 , 36 ]. Concerning sCD163, previously published results of comparable cohorts showed higher concentrations of sCD163 in PLWH under long term ART and undetectable HIV RNA levels compared to age matched HIV-seronegative controls, but none of them was controlled for CMV serostatus [ 5 , 6 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

Assessing the differential impact of chronic CMV and treated HIV infection on CD8+ T-cell differentiation in a matched cohort study: is CMV the key?

et al. 2021

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Background Cytomegalovirus (CMV) infection is one of the main driving forces of T-cell senescence in the general population, whereas its differential impact in people living with HIV (PLWH) is less well characterized. The study explores the effect of latent CMV infection on T-cell subsets, monocyte/macrophages activation markers, and CRP in PLWH on long-term ART. Methods Cross-sectional cohort study including PLWH on long-term suppressive ART. Individuals of 4 groups (HIV+CMV−, HIV+CMV+, HIV−CMV+, and HIV−CMV−) were matched 1:1:1:1 for age and sex. Immunophenotyping of lymphocyte and T-cell subsets by multicolor flow cytometry was performed in fresh blood samples collected from patients and healthy donors. Results Both, latent CMV and treated HIV infection were associated with an expansion of CD8 T cells, a reduced CD4/CD8 ratio, and with CD8 T-cell activation with a cumulative effect in CMV/HIV-coinfected individuals. CMV was associated with elevated numbers of late effector and terminally differentiated CD8 T-cells. Compared to CMV monoinfection, CMV/HIV coinfection showed to be associated with lower proportion of CD28−CD8+ T cells expressing CD57 suggesting that HIV preferentially expands CD28−CD57−CD8+ T cells and impedes terminal differentiation of CD28−CD8+ T cells. We could not show any association between HIV or CMV infection status and concentration of CRP and CD163. Conclusions CMV infection is associated with phenotypic signs of T-cell senescence, promoting exacerbation and persistence of alterations of the T-cell compartment in PLWH on effective ART, which are associated with adverse clinical outcomes and may be an attractive target for therapeutic interventions.

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Proximity of Cytomegalovirus-Specific CD8+ T Cells to Replicative Senescence in Human Immunodeficiency Virus-Infected Individuals

Cited by 11 publications

References 50 publications

Association of Premature Immune Aging and Cytomegalovirus After Solid Organ Transplant

Association of Premature Immune Aging and Cytomegalovirus After Solid Organ Transplant

The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence

Assessing the differential impact of chronic CMV and treated HIV infection on CD8+ T-cell differentiation in a matched cohort study: is CMV the key?

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