他汀类药物对 HIV 共受体 CCR5 和 CXCR4 表达的体内影响。

In vivo effect of statins on the expression of the HIV co-receptors CCR5 and CXCR4.

机构信息

Immunovirology Group, School of Medicine, University of Antioquia, Medellin, Colombia.

Department of Internal Medicine and Academic Group of Clinical Epidemiology (GRAEPIC), School of Medicine, University of Antioquia, Medellín, Colombia ; Clinical Research Unit, Hospital Pablo Tobón Uribe, Medellin, Colombia.

出版信息

AIDS Res Ther. 2013 May 1;10:10. doi: 10.1186/1742-6405-10-10. eCollection 2013.

DOI:10.1186/1742-6405-10-10

PMID:23634877

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3668251/

Abstract

BACKGROUND

During the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are therefore potential targets for therapeutic intervention. Indeed statins, compounds that inhibit cellular synthesis of cholesterol and have anti-inflammatory and immunomodulatory properties were shown to inhibit HIV-1 infection by R5 tropic strains but not by X4 strains in vitro, mainly by altering the chemokine receptor/ligands axes. Therefore, the objective of this study was to characterize in vivo, the capacity of statins to modulate in HIV seronegative and chronically HIV-1-infected adults the expression of CCR5 and CXCR4, of their ligands and the tropism of circulating HIV-1 strains.

METHODS

Samples from asymptomatic HIV-1-infected adults enrolled in a clinical trial aimed at evaluating the antiretroviral activity of lovastatin were used to evaluate in vivo the modulation by lovastatin of CCR5, CXCR4, their ligands, and the shift in plasma viral tropism over one year of intervention. In addition, ten HIV negative adults received a daily oral dose of 40 mg of lovastatin or 20 mg of atorvastatin; seven other HIV negative individuals who received no treatment were followed as controls. The frequency and phenotype of immune cells were determined by flow-cytometry; mRNA levels of chemokine receptors and their ligands were determined by real-time PCR. Viral tropism was determined by PCR and sequencing, applying the clonal and clinical model of analyses.

RESULTS

Our study shows that long-term administration of lovastatin in HIV-infected individuals does not induce a shift in viral tropism, or induce a significant modulation of CCR5 and CXCR4 on immune cells in HIV-infected patients. Similar results were found in HIV seronegative control subjects, treated with lovastatin or atorvastatin, but a significant increase in CCL3 and CCL4 transcription was observed in these individuals.

CONCLUSIONS

These findings suggest that long-term administration of statins at therapeutic doses, does not significantly affect the expression of HIV-1 co-receptors or of their ligands. In addition it is important to point out that based on the results obtained, therapeutic administration of statins in HIV-infected patients with lipid disorders is safe in terms of selecting X4 strains.

摘要

背景

在 HIV-1 复制周期中，包括趋化因子受体和胆固醇在内的几种分子是至关重要的，因此是治疗干预的潜在靶点。事实上，他汀类药物是一种抑制细胞内胆固醇合成的化合物，具有抗炎和免疫调节作用，已被证明可以抑制 R5 嗜性株 HIV-1 的感染，但不能抑制 X4 株 HIV-1 的感染，主要是通过改变趋化因子受体/配体轴。因此，本研究的目的是在 HIV 阴性和慢性 HIV-1 感染的成年人中，描述他汀类药物对 CCR5 和 CXCR4 及其配体的表达以及循环 HIV-1 株的嗜性的体内调节作用。

方法

从参加评估 lovastatin 抗逆转录病毒活性的临床试验的无症状 HIV-1 感染成年人的样本中，我们评估了 lovastatin 在一年的干预期间对 CCR5、CXCR4、其配体以及血浆病毒嗜性转变的体内调节作用。此外，10 名 HIV 阴性成年人每天口服 40mg lovastatin 或 20mg atorvastatin；7 名未接受治疗的其他 HIV 阴性个体作为对照进行随访。通过流式细胞术测定免疫细胞的频率和表型；通过实时 PCR 测定趋化因子受体及其配体的 mRNA 水平。应用克隆和临床分析模型，通过 PCR 和测序测定病毒嗜性。

结果

我们的研究表明，在 HIV 感染者中长期给予 lovastatin 不会诱导病毒嗜性的转变，也不会诱导 HIV 感染者免疫细胞上 CCR5 和 CXCR4 的显著调节。在接受 lovastatin 或 atorvastatin 治疗的 HIV 阴性对照者中也发现了类似的结果，但这些个体的 CCL3 和 CCL4 转录显著增加。