Complementary antiviral efficacy of hydroxyurea and protease inhibitors in human immunodeficiency virus-infected dendritic cells and lymphocytes.
Dendritic cells are susceptible to human immunodeficiency virus (HIV) infection and may transmit the virus to T cells in vivo. Scarce information is available about drug efficacy in dendritic cells because preclinical testing of antiretroviral drugs has been limited predominantly to T cells and macrophages. We compared the antiviral activities of hydroxyurea and two protease inhibitors (indinavir and ritonavir) in monocyte-derived dendritic cells and in lymphocytes. At therapeutic concentrations (50 to 100 microM), hydroxyurea inhibited supernatant virus production from monocyte-derived dendritic cells in vitro but the drug was ineffective in activated lymphocytes. Concentrations of hydroxyurea insufficient to be effective in activated lymphocytes cultured alone strongly inhibited supernatant virus production from cocultures of uninfected, activated lymphocytes with previously infected monocyte-derived dendritic cells in vitro. In contrast, protease inhibitors were up to 30-fold less efficient in dendritic cells than in activated lymphocytes. Our data support the rationale for testing of the combination of hydroxyurea and protease inhibitors, since these drugs may have complementary antiviral efficacies in different cell compartments. A new criterion for combining drugs for the treatment of HIV infection could be to include at least one drug that selectively targets HIV in viral reservoirs.
Piccinini
Giampiero
G
Research Institute for Genetic and Human Therapy, IRCCS Policlinico S. Matteo, Pavia, Italy.
Foli
Andrea
A
Comolli
Giuditta
G
Lisziewicz
Julianna
J
Lori
Franco
F
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology / Q000821:virology*; D015658:HIV Infections / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D019469:Indinavir / Q000494:pharmacology; D008213:Lymphocyte Activation; D019438:Ritonavir / Q000494:pharmacology; D013601:T-Lymphocytes / Q000821:virology*
D017320:HIV Protease Inhibitors; D019469:Indinavir; D019438:Ritonavir; D006918:Hydroxyurea