Rapamycin reduces CCR5 density levels on CD4 T cells, and this effect results in potentiation of enfuvirtide (T-20) against R5 strains of human immunodeficiency virus type 1 in vitro.
The CCR5 chemokine receptor plays a pivotal role in human immunodeficiency virus type 1 (HIV-1) infection. Several studies have suggested that CCR5 density levels in individuals are rate limiting for infection. In addition, CCR5 density levels influence the antiviral activity of the HIV-1 fusion inhibitor enfuvirtide (T-20) against R5 strains. In the present study we demonstrate that rapamycin (RAPA), a drug approved for the treatment of renal transplantation rejection, reduces CCR5 density levels on CD4 T cells and inhibits R5 HIV-1 replication. In addition, RAPA increased the antiviral activity of T-20 against R5 strains of the virus in a cell-cell fusion assay and as shown by quantification of early products of viral reverse transcription. Median-effect analysis of drug interaction between RAPA and T-20 in infectivity assays using donor peripheral blood mononuclear cells demonstrated that the RAPA-T-20 combination is synergistic against R5 strains of HIV-1 and this synergy translates into T-20 dose reductions of up to approximately 33-fold. Importantly, RAPA effects on replication levels and T-20 susceptibility of R5 strains of HIV-1 were observed at drug concentrations that did not inhibit cell proliferation. These results suggest that low concentrations of RAPA may potentiate the antiviral activity of T-20 against R5 strains of HIV-1, which are generally present throughout the course of infection and are less sensitive to T-20 inhibition than are X4 strains.
Heredia
Alonso
A
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA.
Gilliam
Bruce
B
Latinovic
Olga
O
Le
Nhut
N
Bamba
Douty
D
Devico
Anthony
A
Melikyan
Gregory B
GB
Gallo
Robert C
RC
Redfield
Robert R
RR
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D000077560:Enfuvirtide; D005562:Formazans / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D005562:Formazans; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; D019713:Receptors, CCR5; D000077560:Enfuvirtide; D020123:Sirolimus