Statins disrupt CCR5 and RANTES expression levels in CD4(+) T lymphocytes in vitro and preferentially decrease
Alexey A Nabatov1, Georgios Pollakis, Thomas Linnemann
1Laboratory of Experimental Virology, Department of Medical Microbiology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.
Background:
Statins have previously been shown to reduce the in vitro infection of human immunodeficiency virus type 1 (HIV-1) through modulation of Rho GTPase activity and lipid raft formation at the cell surface, as well as by disrupting LFA-1 incorporation into viral particles.
Principle Findings:
Here we demonstrate that treatment of an enriched CD4(+) lymphocyte population with lovastatin (Lov), mevastatin (Mev) and simvastatin (activated and non-activated, Sim(A) and Sim(N), respectively) can reduce the cell surface expression of the CC-chemokine receptor CCR5 (P<0.01 for Sim(A) and Lov). The lowered CCR5 expression was associated with down-regulation of CCR5 mRNA expression. The CC-chemokine RANTES protein and mRNA expression levels were slightly increased in CD4(+) enriched lymphocytes treated with statins. Both R5 and X4 HIV-1 were reduced for their infection of statin-treated cells; however, in cultures where statins were removed and where a decrease in CCR5 expression was observed, there was a preferential inhibition of infection with an R5 versus X4 virus.
Conclusions:
The results indicate that the modulation of CC-chemokine receptor (CCR5) and CC-chemokine (RANTES) expression levels should be considered as contributing to the anti-viral effects of statins, preferentially inhibiting R5 viruses. This observation, in combination with the immunomodulatory activity exerted by statins, suggests they may possess more potent anti-HIV-1 activity when applied during the early stages of infection or in lowering viral transmission. Alternatively, statin treatment could be considered as a way to modulate immune induction such as during vaccination protocols.
Insights
Statins reduce human immunodeficiency virus type 1 (HIV-1) infection by lowering CC-chemokine receptor 5 (CCR5) expression on CD4(+) lymphocytes. This effect preferentially inhibits R5 HIV-1 strains, suggesting statins
Area of Science:
- Immunology
- Virology
- Pharmacology
Background:
- Statins are known to inhibit in vitro human immunodeficiency virus type 1 (HIV-1) infection.
- Mechanisms include modulation of Rho GTPase activity, lipid raft formation, and disruption of LFA-1 incorporation into viral particles.
Purpose of the Study:
- To investigate the effect of statins on CC-chemokine receptor 5 (CCR5) expression in CD4(+) lymphocytes.
- To determine the impact of statin-induced CCR5 modulation on HIV-1 infection.
Main Methods:
- Treatment of CD4(+) lymphocytes with lovastatin, mevastatin, and simvastatin.
- Measurement of cell surface and mRNA expression of CCR5 and RANTES.
- Assessment of HIV-1 (R5 and X4 strains) infection in treated and untreated cells.
Main Results:
- Statins significantly reduced CCR5 expression and mRNA levels in CD4(+) lymphocytes.
- RANTES expression showed a slight increase with statin treatment.
- Statin treatment reduced infection by both R5 and X4 HIV-1 strains, with a preferential inhibition of R5 strains when statins were removed.
Conclusions:
- Modulation of CCR5 and RANTES by statins contributes to their anti-HIV-1 activity, particularly against R5 viruses.
- Statins may be effective in early HIV-1 infection stages or for reducing viral transmission due to their antiviral and immunomodulatory effects.
- Statin treatment could be explored for modulating immune responses, such as in vaccination protocols.
