Higher levels of IL-6, CD4 turnover and Treg frequency are already present before cART in HIV-infected subjects with later low CD4 recovery

Rosado‐Sánchez, Isaac; Jarrín, Inmaculada; Pozo-Balado, María Mar; Pablo-Bernal, Rebeca S. de; Herrero-Fernández, Inés; Álvarez-Ríos, Ana Isabel; Rodríguez-Gallego, Esther; Genebat, Miguel; Vera, Mar; Berenguer, Juan; Martín, María Luisa; Bernal, Enrique; Vidal, Francesc; Blanco, Julià; Leal, Manuel; Pacheco, Yolanda M.

doi:10.1016/j.antiviral.2017.03.015

Cited by 20 publications

(30 citation statements)

References 30 publications

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“…This hypothesis still needs to be demonstrated but is also supported by the strong inverse associations between CD4/CD8 T-cell ratio and turnover-related markers (Ki67 and CD95) as well as the Treg frequency. Note that a CD4/CD8 T-cell ratio lower than 0.1 is associated with an abrupt increase in Treg frequency, and consistently, we have reported a higher Treg frequency and T-cell turnover in LR subjects before cART instauration (12).…”

Section: Discussionsupporting

confidence: 84%

“…We first compared the CD4/CD8 T-cell ratio in pre-cART samples of LR and HR subjects from a previous study where both groups had been frequency matched by sex, age, baseline CD4 counts, and viral load (12). Data for CD8 counts were not available from the source cohort (CoRIS), but CD8 and CD4 T-cell frequencies had been determined by flow cytometry in most samples (19 LR and 19 HR subjects), and such frequencies were used to calculate the CD4/CD8 T-cell ratio.…”

Section: Resultsmentioning

confidence: 99%

“…We selected pre-cART samples of LR subjects and HR subjects from two different sources: (i) from a previous case-control study (12) with LR and HR subjects from CoRIS-BioBank (see the supplemental material for details) and (ii) consecutive LR and HR subjects visiting the Infectious Diseases Service of Virgen del Rocío University Hospital. First, we included LR and HR subjects from a previous study (12) where both groups had been frequency matched by sex, age, baseline CD4 counts, and viral load. For these subjects, peripheral blood mononuclear cell (PBMC) samples were available and flow cytometry had been performed for immunophenotyping, including CD4, CD8, Ki67, CD95, and Treg cells (see the supplemental material for details).…”

Section: Methodsmentioning

confidence: 99%

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A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

Rosado‐Sánchez

Herrero-Fernández

Álvarez-Ríos

et al. 2017

Antimicrob Agents Chemother

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We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.KEYWORDS CD4/CD8 T-cell ratio, delayed cART, low CD4 recovery, T-cell turnover, thymic function, CD4/CD8 ratio, antiretroviral therapy, human immunodeficiency virus, immunodiscordant A pproximately one out of four HIV-infected subjects with delayed combination antiretroviral therapy (cART) initiation persistently maintains low CD4 counts despite suppressive cART (subjects immunodiscordant to cART) and shows increased risk of non-AIDS-related events and mortality (1, 2). Traditional associated risk factors for such anomalous immune responses to cART include age, male sex, low CD4 nadir, injection drug use, and hepatitis C virus (HCV) coinfection (reviewed in references 3 and 4). More recently, a predictive value for baseline CXCR4-tropic HIV variants has also been proposed for both the low CD4 recovery (5) and the emergence of non-AIDSrelated events (6).The HIV infection leads to an inversion of the CD4/CD8 T-cell ratio (7), and globally, the CD4/CD8 T-cell ratio has been associated with clinical progression, independently of CD4 counts (7-9). However, whereas a low baseline CD4 count is undoubtedly associated with immunodiscordance, a potential different meaning of the baseline CD4/CD8 T-cell ratio has not yet been explored. Nevertheless, we have recently reported that CD4/CD8 T-cell ratio is associated with thymic function in antiretroviral-

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Section: Discussionsupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

Rosado‐Sánchez

Herrero-Fernández

Álvarez-Ríos

et al. 2017

Antimicrob Agents Chemother

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“…Accordingly, perturbations in the IL‐7/IL‐7R system may not be a reliable predictor of incomplete immune reconstitution. It has been reported that in HIV‐1‐infected individuals with incomplete immune reconstitution, elevated plasma levels of IL‐6, and increased CD4 + T cell turnover are already present before ART initiation . A study by Shive et al.…”

Section: Potential Mechanisms Of Incomplete Immune Reconstitutionmentioning

confidence: 99%

“…Accordingly, perturbations in the IL-7/IL-7R system may not be a reliable predictor of incomplete immune reconstitution. It has been reported that in HIV-1-infected individuals with incomplete immune reconstitution, elevated plasma levels of IL-6, and increased CD4 + T cell turnover are already present before ART initiation 69,70. A study by Shive et al showed that pre-exposure of PBMCs from healthy subjects to IL-1 or IL-6 can drive CD4 + T cell turnover, downregulate CD127 expression, and diminish CD4 + T-cell responsiveness to IL-7 71.…”

mentioning

confidence: 99%

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

212

214

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The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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The effect of protease inhibitors‐based antiretroviral therapy on serum/plasma interleukin‐6 levels among PLHIV: a systematic review and meta‐analysis

Ashuro

Zhang

Wang

et al. 2022

Journal of Medical Virology

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Recommended treatment regimen for human immune deficiency virus (HIV) infection includes protease inhibitors/ritonavir (PIs/r) combined with twonucleoside reverse-transcriptase inhibitors (2NRTIs), which enable to achieve and maintain viral suppression, restore, and preserve immune function. However, there were inconsistent findings on the levels of interleukin-6 (IL-6) levels. Systematic review and meta-analysis were performed to quantify the pooled effects of PIs/rbased antiretroviral therapy (ART) on serum/plasma IL-6 levels in people living with the HIV (PLHIV). PubMed, Web of Science, and Embase were searched from the earliest record to November 4, 2020. Data analysis was conducted on Stata version 16 and Review Manager 5.3. A random-effect model was used to compute a pooled effect size and weighted mean difference (WMD) was considered the summary effect size. Heterogeneity between studies was estimated by Cochrane's Q test (χ 2 test) and I 2 statistic and subgroup analysis were performed to explore the source of heterogeneity. Initial search identified 3098 records and 5 studies (7 trials) met inclusion criteria. The pooled mean difference in serum/plasma IL-6 levels from baseline to follow-up was 0.534 pg/ml (95% confidence interval: −0.012, 1.08, P = 0.05, I 2 = 76.4%). In subgroup analysis, there was a significant association between increased serum/plasma IL-6 levels and age group ≥ 35 years old, baseline CD4 + counts < 350 cell/mm 3 , and mean viral load ≥ 4.5 log10 copies/ml. We found that serum/plasma IL-6 levels increased after combined ART among treatment-naïve individuals who initiated a successful combination of PIs/r with 2NRTIs. This result also highlights the need to monitor serum/plasma IL-6 levels during antiviral therapy, which may aid in the effective future treatment of systemic inflammation and related disorders following elevated IL-6 levels.

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Higher levels of IL-6, CD4 turnover and Treg frequency are already present before cART in HIV-infected subjects with later low CD4 recovery

Cited by 20 publications

References 30 publications

A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

The effect of protease inhibitors‐based antiretroviral therapy on serum/plasma interleukin‐6 levels among PLHIV: a systematic review and meta‐analysis

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