The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults

Sainz, Talía; Serrano‐Villar, Sergio; Díaz, Laura; Tomé, María Isabel González; Gurbindo, María Dolores; José, María Isabel de; Mellado, María José; Ramos, José Tomás; Zamora, Javier; Moreno, Santiago; Muñoz‐Fernández, María Ángeles

doi:10.1097/qad.0b013e32835faa72

Cited by 134 publications

(121 citation statements)

References 17 publications

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“…Today, it is widely known that in many cases, despite fully recovered CD4 counts after long-term ART, the CD4/CD8 ratio rarely reaches normal levels. The reason for this is unknown, but recent data from HIV-infected children, adolescents, and adults who were receiving ART have shown strong associations between the CD4/CD8 ratio and T cell activation, senescence, and activation/ exhaustion (23,24). All of our diverse analyses confirm that the CD4/CD8 ratio is a better surrogate of combined T cell pathogenesis than the CD4 count and VL.…”

Section: Discussionsupporting

confidence: 52%

“…Recent data from both HIV-infected children and adults have shown strong associations between the CD4/CD8 ratio and T cell activation, senescence, and activation/exhaustion in patients receiving ART (23,24). However, multiparametric analyses that combine memory CD4 + and CD8 + T cell activation, exhaustion, and senescence markers have not been conducted and correlated with the currently measured routine laboratory parameters.…”

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confidence: 99%

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Multiparametric Bioinformatics Distinguish the CD4/CD8 Ratio as a Suitable Laboratory Predictor of Combined T Cell Pathogenesis in HIV Infection

Buggert

Frederiksen

Noyan

et al. 2014

The Journal of Immunology

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HIV disease progression is characterized by numerous pathological changes of the cellular immune system. Still, the CD4 cell count and viral load represent the laboratory parameters that are most commonly used in the clinic to determine the disease progression. In this study, we conducted an interdisciplinary investigation to determine which laboratory parameters (viral load, CD4 count, CD8 count, CD4 %, CD8 %, CD4/CD8) are most strongly associated with pathological changes of the immune system. Multiparametric flow cytometry was used to assess markers of CD4+ and CD8+ T cell activation (CD38, HLA-DR), exhaustion (PD-1, Tim-3), senescence (CD28, CD57), and memory differentiation (CD45RO, CD27) in a cohort of 47 untreated HIV-infected individuals. Using bioinformatical methods, we identified 139 unique populations, representing the “combined T cell pathogenesis,” which significantly differed between the HIV-infected individuals and healthy control subjects. CD38, HLA-DR, and PD-1 were particularly expressed within these unique T cell populations. The CD4/CD8 ratio was correlated with more pathological T cell populations (n = 10) and had a significantly higher average correlation coefficient than any other laboratory parameters. We also reduced the dimensionalities of the 139-unique populations by Z-transformations and principal component analysis, which still identified the CD4/CD8 ratio as the preeminent surrogate of combined T cell pathogenesis. Importantly, the CD4/CD8 ratio at baseline was shown to be significantly associated with CD4 recovery 2 y after therapy initiation. These results indicate that the CD4/CD8 ratio would be a suitable laboratory predictor in future clinical and therapeutic settings to monitor pathological T cell events in HIV infection.

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 99%

Multiparametric Bioinformatics Distinguish the CD4/CD8 Ratio as a Suitable Laboratory Predictor of Combined T Cell Pathogenesis in HIV Infection

Buggert

Frederiksen

Noyan

et al. 2014

The Journal of Immunology

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“…This is important as incomplete recovery of CD4/CD8 ratio is associated with increased mortality and morbidity during HIV infection [8].…”

Section: Discussionmentioning

confidence: 99%

“…Even in the setting of normal CD4 + counts among treated HIV-infected persons, low CD4/CD8 is associated with poor clinical outcomes [5,6], T-cell dysfunction [6][7][8], and increased inflammation (eg, interleukin 6, C-reactive protein, soluble CD14) [6,9]. These data suggest that CD8 + T-cell expansion might be a driver of increased morbidity and mortality [6,10].…”

mentioning

confidence: 99%

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

et al. 2016

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Background. A low CD4/CD8 ratio in human immunodeficiency virus (HIV)-infected individuals is associated with inflammation and higher risk of non-AIDS morbidity and mortality. In this study, we investigated the effect of subclinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) replication on CD4 + and CD8 + T-cell dynamics when antiretroviral therapy (ART) is started during early infection.Methods. We investigated 604 peripheral blood mononuclear cell samples from 108 CMV-and EBV-seropositive HIV-infected men who have sex with men, who started ART within a median of 4 months from their estimated date of infection and were followed for a median of 29.1 months thereafter. Levels of CMV and EBV DNA were measured at each timepoint. Mixed-effects asymptotic regression models were applied to characterize CD4 + and CD8 + T-cell dynamics, and Bayesian hierarchical models were used to quantify individual differences in CMV and EBV DNA replication.Results. Higher levels of subclinical CMV replication were associated with lower predicted maximum levels of CD4/CD8 ratio (P < .05), which was driven by higher levels of CD8 + T-cell counts (P < .05), without affecting CD4 + T-cell counts (P > .1). Age was negatively associated with CD4/CD8 levels (P < .05), and this effect was independent of the CMV association (P < .05 for both CMV and age in a multivariate model).Conclusions. Subclinical CMV replication in blood cells during early HIV infection and younger age were associated with lower CD4/CD8 ratios during suppressive ART. These findings suggest that active CMV infection in the setting of treated HIV may represent an attractive potential target for therapeutic intervention.

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“…34 Allers et al found an increased effector memory phenotype in older HIV patients associated to an increased inflammatory cytokines. 6 The reduced CD4/CD8 ratio, 47 the decreased expression of CD28, the shift from na€ ıve to central memory cells and the reduction of TCR repertoire is much more evident in HIV-infected patients before the introduction of HAART. 8 However HAART is not able to normalize these phenomena.…”

Section: Immunology Of Aging In Hiv-infected Patientsmentioning

confidence: 99%

Immunosenescence and hurdles in the clinical management of older HIV-patients

2017

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People living with HIV (PLWH) who are treated with effective highly active antiretroviral therapy (HAART) have a similar life expectancy to the general population. Moreover, an increasing proportion of new HIV diagnoses are made in people older than 50 y. The number of older HIVinfected patients is thus constantly growing and it is expected that by 2030 around 70% of PLWH will be more than 50 y old. On the other hand, HIV infection itself is responsible for accelerated immunosenescence, a progressive decline of immune system function in both the adaptive and the innate arm, which impairs the ability of an individual to respond to infections and to give rise to long-term immunity; furthermore, older patients tend to have a worse immunological response to HAART.In this review we focus on the pathogenesis of HIV-induced immunosenescence and on the clinical management of older HIV-infected patients.

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The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults

Cited by 134 publications

References 17 publications

Multiparametric Bioinformatics Distinguish the CD4/CD8 Ratio as a Suitable Laboratory Predictor of Combined T Cell Pathogenesis in HIV Infection

Multiparametric Bioinformatics Distinguish the CD4/CD8 Ratio as a Suitable Laboratory Predictor of Combined T Cell Pathogenesis in HIV Infection

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

Immunosenescence and hurdles in the clinical management of older HIV-patients

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