Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study.

Abstract

Human immunodeficiency virus type 1 (1IV-1) strains were Isolated from nine patients before and after prolonged therapy with either an alternating regimen of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dldeoxycytldin (ddC) (AZT/ddC) or 2',3'-deoxyinosine (ddl) alone. AN strains obtained from four patients who received AZT/ddC for up to 41 mo were highly insensitive to AZT in vitro. Only one strain obtained after AZT/ddC therapy showed reduced susceptibility to ddC in addition to AZT and had previously unreported amino acid substitutions in the viral polymeraseending pol region, whereas three other strains had one or more of the five previously reported AZT-related mutations. In flve HIV-1 strains from patents who received ddI for up to 29 mo, no appreciable decrease in sensitivity to ddl was detect.Two strains Isolated after ddI therapy had no t amino acid mutations, although three strains had a mutation reportedly acited with ddI administration. These data suggest that HIV-1 develops reduced susceptibility to AZT more readily than to ddC and ddI and/or that the reduced susceptibility to ddC and ddI is modest in degree. Moreover, the present data suggest that an alternating regimen of AZT and ddC does not block the emergence of AZT-ensitve va . It should be noted, however, that the current results do not provide a basds for concluding that AZT/ddC or ddI is inferior, equivalent, or superior to AZT as therapy of AIDS.

Novel Low Molecular Weight Spirodiketopiperazine Derivatives Potently Inhibit R5 HIV-1 Infection through Their Antagonistic Effects on CCR5

“…A panel of HIV-1 was employed for drug susceptibility assays: HIV-1 LAI (14), HIV-1 NL4 -3 (15), HIV-1 BaL (16), HIV-1 89.6 (17), and HIV-1 ERS104pre (a clinical HIV-1 strain isolated from a drug-naive AIDS patient (18)). Four clinical HIV-1 strains, HIV-1 JSL , HIV-1 MM , HIV-1 TM , and HIV-1 MOKW , were also employed.…”

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

“…Those mutations that confer moderate (4-to Ͻ50-fold) levels of phenotypic resistance to 3TC reported previously always appeared in the context of a constellation of mutations that confer resistance to multiple nucleoside analogues or as a cross-resistance phenomenon that appears with the emergence of resistance to another nucleoside analogue. This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2, 17, 29).…”

Efficacy of Dideoxynucleosides against Human Foamy Virus and Relationship to Its Reverse Transcriptase Amino Acid Sequence and Structure

“…In the case of ZDV, which exhibited the same activity level on HFV and HIV-1, we did not find any of the amino acid residues involved in HIV-1 resistance to the drug at positions 41, 67, 70, 215, and 219 (12), corresponding to positions 91, 118, 121, 252, and 256 of the HFV RT. In addition, neither multidrug resistance mutations (Q151 M profile) (22,23) nor a position 69 insertion (J. J. de Jong, S. Jurriaans, J. Goudsmit, E. Baan, R. Huismans, S. A. Danner, M. E. Hillebrand, J. H. ten Veen, and F. de Wolf, Antivir. Ther., abstr.…”