Abstract：
:Maraviroc, the only CCR5 antagonist HIV inhibitor currently approved, has potent antiviral activity in treatment-experienced individuals infected with CCR5-using HIV-1 (R5 HIV-1). However, recent data from the MOTIVATE trials indicate that R5 HIV-1 can develop resistance to Maraviroc, underscoring the need for additional CCR5 antagonists. The CCR5 antagonist aplaviroc (APL) is active against Maraviroc-resistant viral strains but its clinical development has ended because of dose-related toxicity. Here we demonstrate that reduction of CCR5 density (receptors/cell) with the immunomodulatory drug rapamycin (RAPA) enhances the antiviral activity of APL, allowing lower, non-toxic effective doses. In the presence of RAPA, the concentration of APL required for 90% inhibition of R5 HIV-1 in primary CD4 lymphocytes was reduced by as much as 25-fold. We conclude that low doses of RAPA may reduce the anti-HIV effective dose of APL-derivatives currently in development and thus minimize their potential toxicity. Combinations of RAPA and CCR5 antagonists could provide an effective means to control drug-resistant R5 HIV in patients, most notably those infected with Maraviroc-resistant viruses.
journal_name
Antiviral Resjournal_title
Antiviral researchauthors
Latinovic O,Heredia A,Gallo RC,Reitz M,Le N,Redfield RRdoi
10.1016/j.antiviral.2009.02.199subject
Has Abstractpub_date
2009-07-01 00:00:00pages
86-9issue
1eissn
0166-3542issn
1872-9096pii
S0166-3542(09)00242-3journal_volume
83pub_type
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