Research Article: In vivo effect of statins on the expression of the HIV co-receptors CCR5 and CXCR4

Date Published: May 1, 2013

Publisher: BioMed Central

Author(s): Edwin A Higuita, Fabián A Jaimes, Maria T Rugeles, Carlos J Montoya.

http://doi.org/10.1186/1742-6405-10-10

Abstract

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.

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.

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.

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.

Partial Text

Despite the fact that highly active antiretroviral therapy (HAART) is a clinically accepted and cost-effective intervention [1], its efficiency is hampered by limitations in therapy adherence and the emergence of viral resistance, facts closely related to adverse effects and toxicity [2,3]. Thus, it is necessary to develop new medications and therapeutic strategies, with novel mechanisms of action to overcome the limitations of HAART.

In this investigation, evaluating a representative cohort of chronic asymptomatic HIV-1-infected patients without requirements to receive antiretroviral therapy, we demonstrated that a daily oral administration of lovastatin during one year did not result in significant modulation of CCR5 and CXCR4 expression on CD4+ T cells or CD4+ monocytes. Also, in HIV negative individuals, the daily administration of two different statins for 45 days did not lead to a significant regulation of these molecules. These findings suggest that long-term administration of statins, at doses commonly used in clinical practice, does not have a significant effect on modulating the expression of HIV-1 co-receptors or their ligands (except for CCL3 and CCL4).

EAH received a doctoral scholarship from COLCIENCIAS; the other authors declare that they have no competing interest.

EA was the primary researcher, conceived the study, designed, participated in data collection and drafted manuscript, FJ assigned the randomization of patients and conducted statistical analysis, MR and CM assisted in data collection, follow-up the HIV positive patients and reviewed the initial and final drafts of the manuscript. All authors read and approved the final manuscript.

 

Source:

http://doi.org/10.1186/1742-6405-10-10

 

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