OBJECTIVES: Because recent evidence indicates that human immunodeficiency virus type 1 (HIV-1) propagates in resting T lymphocytes in vivo, we wanted to evaluate the antiviral effects exerted by currently used nucleoside (NRTI) and non-nucleoside analog reverse transcription inhibitors in resting lymphocytes, and compare those effects to the ones obtained in activated lymphocytes. METHODS: Tissue culture antiviral assays in which target cells are lymphocytes present in a resting or activated state. Virus replication was measured by a reverse transcription (RT) assay. Cell viability was evaluated using a commercial 3-(4k5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: In vitro results obtained with concentrations of zidovudine and stavudine equivalent to drug levels found in plasma, showed more than 99% HIV-1 inhibition in activated lymphocytes but less than 50% virus inhibition in resting lymphocytes. Conversely, plasma levels of didanosine-inhibited HIV-1 by approximately 50% and 98% in activated and resting lymphocytes, respectively. Plasma level concentration of zalcitabine, lamivudine, and abacavir inhibited viral replication by more than 90% in both resting and activated cells. CONCLUSIONS: These data demonstrate that specific NRTI antiretroviral agents have different activity against HIV RT, depending on the state of cell cycle of the infected cell. We suggest that the replication of HIV-1 in resting lymphocytes should be taken into account in the design of future clinical trials, as well as treatment antiretroviral regimens. Selection of combination RTIs so that they provide antiretroviral activity in both resting and activated lymphocytes may be a way to minimize treatment failure and the emergence of drug-resistant variants.
OBJECTIVES: Because recent evidence indicates that human immunodeficiency virus type 1 (HIV-1) propagates in resting T lymphocytes in vivo, we wanted to evaluate the antiviral effects exerted by currently used nucleoside (NRTI) and non-nucleoside analog reverse transcription inhibitors in resting lymphocytes, and compare those effects to the ones obtained in activated lymphocytes. METHODS: Tissue culture antiviral assays in which target cells are lymphocytes present in a resting or activated state. Virus replication was measured by a reverse transcription (RT) assay. Cell viability was evaluated using a commercial 3-(4k5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: In vitro results obtained with concentrations of zidovudine and stavudine equivalent to drug levels found in plasma, showed more than 99% HIV-1 inhibition in activated lymphocytes but less than 50% virus inhibition in resting lymphocytes. Conversely, plasma levels of didanosine-inhibited HIV-1 by approximately 50% and 98% in activated and resting lymphocytes, respectively. Plasma level concentration of zalcitabine, lamivudine, and abacavir inhibited viral replication by more than 90% in both resting and activated cells. CONCLUSIONS: These data demonstrate that specific NRTI antiretroviral agents have different activity against HIV RT, depending on the state of cell cycle of the infected cell. We suggest that the replication of HIV-1 in resting lymphocytes should be taken into account in the design of future clinical trials, as well as treatment antiretroviral regimens. Selection of combination RTIs so that they provide antiretroviral activity in both resting and activated lymphocytes may be a way to minimize treatment failure and the emergence of drug-resistant variants.