The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression

Serrano‐Villar, Sergio; Gutiérrez, Carolina; Vallejo, Alejandro; Hernández-Novoa, Beatriz; Díaz, Laura; Fernández, María Abad; Madrid, Nadia; Dronda, Fernando; Zamora, Javier; Muñoz‐Fernández, María Ángeles; Moreno, Santiago

doi:10.1016/j.jinf.2012.09.013

Cited by 131 publications

(106 citation statements)

References 42 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: 53%

“…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: 53%

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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“…CD8 + T-cell persistence in treated HIV-infected donors contributes to abnormally low ratios of CD4 + T cells to CD8 + T cells (hereafter, "CD4 + /CD8 + ratios"), now recognized as associated with a greater risk for morbidity, including cardiovascular events [2][3][4][5]. A relationship to vascular health is suggested by observations that an inverted CD4 + /CD8 + ratio is also associated with greater intima media thickness and arterial stiffness, both of which are important predictors of cardiovascular morbidity [4,6].…”

Section: Human Immunodeficiency Virus (Hiv) Infection Results In a Mamentioning

confidence: 99%

“…A recent study examined the characteristics of the expanded circulating CD8 + T cells in patients with inverted CD4 + /CD8 + ratios despite sustaining CD4 + T-cell counts at >500 cells/µL during ART [3]. Inverted CD4 + /CD8 + ratios were associated with higher indices of CD8 + T-cell activation, exhaustion, and immunosenescence [2,3], and we have linked cytomegalovirus (CMV) coinfection to inflammation, CD8 + T-cell expansion, and inverted CD4 + /CD8 + ratios in ART-treated HIV infection [7]. While CD8 + T-cell expansion in ART-treated HIV infection has been associated with cardiovascular disease (CVD), neither the drivers of CD8 + lymphocytosis in this setting nor the underlying mechanisms for their link to increased cardiovascular risk are fully understood [1].…”

Section: Human Immunodeficiency Virus (Hiv) Infection Results In a Mamentioning

confidence: 99%

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

et al. 2016

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Increases in inflammation, coagulation, and CD8 + T-cell numbers are associated with an elevated cardiovascular disease (CVD) risk in human immunodeficiency virus (HIV)-infected antiretroviral therapy (ART) recipients. Circulating memory CD8 + T cells that express the vascular endothelium-homing receptor CX3CR1 (fractalkine receptor) are enriched in HIV-infected ART recipients. Thrombin-activated receptor (PAR-1) expression is increased in HIV-infected ART recipients and is particularly elevated on CX3CR1 + CD8 + T cells, suggesting that these cells could interact with coagulation elements. Indeed, thrombin directly enhanced T-cell receptor-mediated interferon γ production by purified CD8 + T cells but was attenuated by thrombin-induced release of transforming growth factor β by platelets. We have therefore identified a population of circulating memory CD8 + T cells in HIV infection that may home to endothelium, can be activated by clot-forming elements, and are susceptible to platelet-mediated regulation. Complex interactions between inflammatory elements and coagulation at endothelial surfaces may play an important role in CVD risk in HIV-infected ART recipients.

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“…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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The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression

Cited by 131 publications

References 42 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

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

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

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The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression

Cited by 131 publications

References 42 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

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

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

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Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions