Differential human immunodeficiency virus-suppressive activity of reverse transcription inhibitors in resting and activated peripheral blood lymphocytes - Implications for therapy

Objectives: Because recent evidence indicates that human immunodeficiency v irus type I (HIV-1) propagates in resting T lymphocytes in vivo, we wanted to evaluate the antiviral effects exerted by currently used nucleoside (NRT I) and nonnucleoside analog reverse transcription inhibitors in resting lym phocytes, and compare those effects to the ones obtained in activated lymph ocytes. Methods: Tissue culture antiviral assays in which target cells are lymphocy tes present in a resting or activated state. Virus replication was measured by a reverse transcription (R:I) assay. Cell viability was evaluated using a commercial 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: In vitro results obtained with concentrations of zidovudine and st avudine equivalent to drug levels found in plasma, showed more than 99% HIV -1 inhibition in activated lymphocytes but less than 50% virus inhibition i n resting lymphocytes. Conversely, plasma levels of didanosine-inhibited HI V-1 by approximately 50% and 98% in activated and resting lymphocytes, resp ectively. Plasma level concentrations of zal-citabine, lamivudine, and abac avir inhibited viral replication by more than 90% in both resting and activ ated cells, Conclusions: These data demonstrate that specific NRTI antiretroviral agent s have different activity against HIV RT, depending on the state of cell cy cle of the infected cell. We suggest that the replication of HIV-1 in resti ng lymphocytes should be taken into account in the design of future clinica l trials, as well as treatment antiretroviral regimens. Selection of combin ation RTIs so that they provide antiretroviral activity in both resting and activated lymphocytes may be a way to minimize treatment failure and the e mergence of drug-resistant variants.