Dataset Information

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy.

ABSTRACT:

Objective

We evaluated frequencies of T cells with high PD-1 expression (PD-1) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses.

Methods

We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N?=?99). We assessed PD-1 T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels.

Results

Pre-ART, PD-1 CD4 T cells correlated positively with viremia and negatively with CD4 T-cell count. At year 1 on-ART, %PD-1 CD4 T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1 CD8 T cells on-ART remained similar to pre-ART. PD-1 CD4 T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4 T-cell activation on-ART. PD-1 CD4 T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1 CD8 T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV.

Conclusion

PD-1 T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity.

SUBMITTER: Macatangay BJC

PROVIDER: S-EPMC7313719 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy.

Macatangay Bernard J C BJC Gandhi Rajesh T RT Jones Richard B RB Mcmahon Deborah K DK Lalama Christina M CM Bosch Ronald J RJ Cyktor Joshua C JC Thomas Allison S AS Borowski Luann L Riddler Sharon A SA Hogg Evelyn E Stevenson Eva E Eron Joseph J JJ Mellors John W JW Rinaldo Charles R CR

AIDS (London, England) 20200101 1

<h4>Objective</h4>We evaluated frequencies of T cells with high PD-1 expression (PD-1) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses.<h4>Methods</h4>We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N = 99). We assessed PD-1 T-cell frequencies at timepoints pre-ART an ...[more]

PMID: 31634201

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Project description:BackgroundThere is very little data on long-term immune recovery responses in patients on suppressive antiretroviral therapy (ART) in the setting of sub-Saharan Africa (SSA). Thus, we sought to determine CD4+ T-cell, CD8+ T-cell and CD4/CD8 ratio responses in a cohort of HIV infected individuals on sustained suppressive ART followed up for more than a decade.MethodsThe cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 14 years. Trends in median CD4+ T-cells, CD8+ T-cells and CD4/CD8 ratio were reviewed retrospectively. Poisson regression models were used to identify factors associated with achieving normalized T-cell biomarkers. Kaplan-Meier curves were used to estimate the probability of attaining normalized counts while on suppressive ART.ResultsA total of 227 patients with a median duration of follow-up on ART of 12 (IQR: 10.5-13.0) years were included. CD4 cell count increased from baseline median of 138 cells (IQR: 70-202) to 555 cells (IQR: 417-830). CD4 cell increased continuously up until 5 years, after which it plateaued up until 14 years of follow up. Only 69.6% normalized their CD4 cell count within a median of 6.5 (IQR: 3.0-10.5) years. In addition, only 15.9% of the cohort were able to achieve the median reference CD4+ T-cell threshold count in Ethiopians (≈760 cells/μL). CD8+ T-cell counts increased initially until year 1, after which continuous decrease was ascertained. CD4/CD8 ratio trend revealed continuous increase throughout the course of ART, and increased from a median baseline of 0.14 (IQR: 0.09-0.22) to a median of 0.70 (IQR: 0.42-0.95). However, only 12.3% normalized their ratio (≥ 1.0) after a median of 11.5 years. In addition, only 8.8% of the cohort were able to achieve the median reference ratio of healthy Ethiopians.ConclusionDetermination of both CD4+ and CD8+ T-cells, along with CD4/CD8 ratio is highly relevant in long-term follow-up of patients to assess immune recovery. Monitoring ratio levels may serve as a better biomarker risk for disease progression among patients on long-term ART. In addition, the findings emphasize the relevance of initiation of ART at the early stage of HIV-1 infection.

Project description:Human immunodeficiency virus (HIV)-induced changes in immune cells during the acute phase of infection can cause irreversible immunological damage and predict the rate of disease progression. Antiretroviral therapy (ART) remains the most effective strategy for successful immune restoration in immunocompromised people living with HIV and the earlier ART is initiated after infection, the better the long-term clinical outcomes. Here we explored the effect of ART on peripheral antigen presenting cell (APC) phenotype and function in women with HIV-1 subtype C infection who initiated ART in the hyperacute phase (before peak viremia) or during chronic infection. Peripheral blood mononuclear cells obtained longitudinally from study participants were used for immunophenotyping and functional analysis of monocytes and dendritic cells (DCs) using multiparametric flow cytometry and matched plasma was used for measurement of inflammatory markers IL-6 and soluble CD14 (sCD14) by enzyme-linked immunosorbent assay. HIV infection was associated with expansion of monocyte and plasmacytoid DC (pDC) frequencies and perturbation of monocyte subsets compared to uninfected persons despite antiretroviral treatment during hyperacute infection. Expression of activation marker CD69 on monocytes and pDCs in early treated HIV was similar to uninfected individuals. However, despite early ART, HIV infection was associated with elevation of plasma IL-6 and sCD14 levels which correlated with monocyte activation. Furthermore, HIV infection with or without early ART was associated with downmodulation of the co-stimulatory molecule CD86. Notably, early ART was associated with preserved toll-like receptor (TLR)-induced IFN-α responses of pDCs. Overall, this data provides evidence of the beneficial impact of ART initiated in hyperacute infection in preservation of APC functional cytokine production activity; but also highlights persistent inflammation facilitated by monocyte activation even after prolonged viral suppression and suggests the need for therapeutic interventions that target residual immune activation.

Dataset Information

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy.

Objective

Methods

Results

Conclusion

Publications

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy.

Similar Datasets

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