Abstract
BackgroundDuring 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.MethodsSamples 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.ResultsOur 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.ConclusionsThese 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.
Highlights
During the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are potential targets for therapeutic intervention
HIV infection involves an initial interaction between the viral envelope glycoprotein gp120 and the CD4 molecule on the surface of target cells, followed by a second interaction with a co-receptor; for HIV-1, the classical co-receptor function is provided by one of two different molecules, the C-C chemokine receptor 5 (CCR5) or the C-X-C chemokine receptor 4 (CXCR4), which have a normal physiological function serving as receptors for soluble chemokines [4,5]
Tropism To determine the in vivo effect of lovastatin on the shift in viral tropism in HIV-1 infected subjects, a total of 91 DNA samples corresponding to month 0, and of 72 DNA samples corresponding to month 12 after daily administration of lovastatin, were amplified and sequenced
Summary
During the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are potential targets for therapeutic intervention. 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. Some molecules with ability to exert a non-competitive, allosteric, inhibition of the CCR5 receptor have been identified; among them, maraviroc is the first CCR5 antagonist approved for clinical use in HIV-infected patients, and its efficiency has been established in clinical trials [9,10]. Before receiving maraviroc, it is mandatory to first identify the co-receptor used by the strains infecting each patient, due to the risk on selecting the more pathogenic strains that use the CXCR4 co-receptor
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
