Down-Regulation of the Longevity-Associated Protein SIRT1 in Peripheral Blood Mononuclear Cells of Treated HIV Patients.

Aleksandra Gruevska,Juan V Esplugues,Ana Blas-García,María J Galindo,Ángela B Moragrega,Nadezda Apostolova

doi:10.3390/cells11030348

Abstract

The activity of sirtuin 1 (SIRT1), a class III histone deacetylase with a critical role in several biological functions, decreases with age and its deficiency is associated with many inflammatory and age-related diseases. It also regulates the chronic immune activation and viral latency during an HIV infection. The life-span and particularly the health span of HIV patients are substantially shortened; however, the participation of SIRT1 in these effects is not clear. We performed a prospective cross-sectional monocentric study that included 70 HIV-infected patients and 43 BMI-, age- and sex-matched uninfected individuals. We found that in the PBMCs of the HIV patients, SIRT1 mRNA levels were significantly lower (p < 0.0001). This decrease, which was corroborated at the protein level, occurred irrespectively of the antiretroviral regimen these patients received and was not significantly related to the general, HIV-related or comorbidity-related parameters. The levels of the major mitochondrial sirtuin SIRT3 were not altered. Moreover, the strong correlations of SIRT1 with the leukocyte markers CD8A and CD19 present in the uninfected individuals were absent in the HIV patients. In conclusion, this study showed that the PBMCs of the HIV patients displayed diminished SIRT1 levels and altered correlations of SIRT1 with markers of CD8+ T cells and B cells, findings which may be relevant for understanding the complex pathogenic milieu in HIV patients.

Highlights

Due to the effectiveness and safety of combined antiretroviral therapy, HIV infection has become a manageable, life-long disease [1]
We found that while the control individuals showed a weak albeit significant positive correlation in sirtuin 1 (SIRT1)/SIRT3 expression, it was absent in the HIV patients
We found that the HIV patients had higher levels of the acetylated form of histone H3 (H3K9) (Figure 1f), which is in line with the lower SIRT1 expression found in these individuals

Summary

Introduction

Due to the effectiveness and safety of combined antiretroviral therapy (cART), HIV infection has become a manageable, life-long disease [1]. Sirtuins are a subject of increasing attention due to their protective roles in various pathophysiological processes, including aging, neurodegeneration, obesity, heart disease, inflammation and cancer [6]. Besides its widely studied role as a metabolic sensor and regulator, more recently SIRT1 has been acknowledged as a key modulator of the inflammatory reactions and the immune response, including both the innate and the acquired components. It possesses anti-inflammatory functions primarily by inhibiting the transcriptional activities of pro-inflammatory factors through deacetylation and regulates immune cell differentiation in a cell-type-specific manner. At a reduced SIRT1 level, FOXO1 was found to be degraded and the CD8+ T cells had enhanced glycolytic and cytotoxic capacities, resulting in immune dysfunction [9]

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