Important note: Information in this article was accurate in October 2003. The state of the art may have changed since the publication date. |
AIDSWEEKLY Plus; Monday, October 27, 2003
Staff Medical Writers
"Propagation of R5 strains of HIV-1 on CD4 lymphocytes and macrophages requires expression of the CCR5 coreceptor on the cell surface," scientists in the United States explained. "Individuals lacking CCR5 (CCR5Delta32 homozygous genotype) are phenotypically normal and resistant to infection with HIV-1. CCR5 expression on lymphocytes depends on signaling through the IL-2 receptor."
Using flow cytometry analysis, A. Heredia and colleagues at the University of Maryland demonstrated that "rapamycin (RAPA), a drug that disrupts IL-2 receptor signaling, reduces CCR5 surface expression on T cells at concentrations as low as 1 nM."
"In addition, lower concentrations of RAPA (0.01 nM) were sufficient to reduce CCR5 surface expression on maturing monocytes," they found. 'PCR analysis on peripheral blood mononuclear cells (PBMCs) showed that RAPA interfered with CCR5 expression at the transcriptional level."
"Reduced expression of CCR5 on PBMCs cultured in the presence of RAPA was associated with increased extracellular levels of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta," test results revealed. "In infectivity assays, RAPA suppressed the replication of R5 strains of HIV-1 both in PBMC and macrophage cultures."
"In total PBMC cultures, RAPA-mediated inhibition of CCR5-using strains of HIV-1 occurred at 0.01 nM, a concentration of drug that is approximately 103 times lower than therapeutic through levels of drug in renal transplant recipients," according to the report. "In addition, RAPA enhanced the antiviral activity of the CCR5 antagonist TAK-779."
"These results suggest that low concentrations of RAPA may have a role in both the treatment and prevention of HIV-1 infection," the researchers concluded.
Heredia and colleagues published their findings in the Proceedings of the National Academy of Sciences USA (Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: An approach to suppress R5 strains of HIV-1. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10411-6.
Additional information can be obtained by contacting R.R. Redfield, University of Maryland, Biotechnology Institute, Institute of Human Virology, Baltimore, MD 21201 USA.
The publisher of the journal Proceedings of the National Academy of Sciences USA can be contacted at: National Academy of Sciences, 2101 Constitution Avenue NW, Washington, DC 20418 USA.
The information in this article comes under the major subject areas of AIDS & HIV, Immunology, Proteomics, Receptor Studies and Virology.
This article was prepared by AIDS Weekly editors from staff and other reports.
Reference
Heredia A, Amoroso A, Davis C, Le N, et al., "Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1", Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10411-6
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