Resistance pathways of human immunodeficiency virus type 1 against the combination of zidovudine and lamivudine

Abstract

A better understanding of human immunodeficiency virus type 1 drug-resistance evolution under the selective pressure of combination treatment is important for the design of long-term effective treatment strategies. We applied Bayesian network learning to sequences from patients treated with the reverse transcriptase inhibitor combination of zidovudine (AZT) and lamivudine (3TC) to identify the role of many treatment-selected mutations in the development of resistance. Based on the Bayesian network structure, an in vivo fitness landscape was built, reflecting the necessary selective pressure under treatment, to evolve naive sequences to sequences obtained from patients treated with the combination. This landscape, combined with an evolutionary model, was used to predict resistance evolution in longitudinal sequence pairs. In our analysis, mutations 41L, 70R, 184V and 215F/Y were identified as major resistance mutations to the combination of AZT and 3TC, as they were associated directly with treatment experience. The network also suggested a possible role in resistance development for a number of novel mutations. Estimated fitness, using the landscape, correlated significantly with in vitro resistance phenotype in genotypephenotype pairs (R 2 50.70). Variation in predicted evolution under selective pressure correlated significantly with observed in vivo evolution during AZT plus 3CT treatment. In conclusion, we confirmed current knowledge on resistance development to the combination of AZT and 3CT, but additional novel mutations were identified. Moreover, a model to predict resistance evolution during AZT and 3CT treatment has been built and validated.

Use of Proviral DNA to Investigate Virus Resistance Mutations in HIV-infected Zimbabweans

“…One of the sequences had all TAM-1 mutations, and another had all TAM-2 mutations Table 4 Two of these TAMS: D67N and T215K were also observed in a study recently carried out in Zimbabwe [17]. TAMS mainly occur less commonly in patients receiving regimens with TDF and abacavir (ABC) [30]. Initiating treatment with ABC and TDF as part of the drug regimen may reduce occurrence of these mutations.…”

Characterization of amino acids Arg, Ser and Thr at position 70 within HIV-1 reverse transcriptase

“…19 Following a previously described methodology, clinical data were pooled from the HIV Drug Resistance Database (Stanford University, CA, USA), the University Hospital Leuven (Belgium) and Hospital Egaz Moniz (Lisbon, Portugal). 19,20 The analysis included viral isolates spanning the RT region that were sampled from HIV-1 patients receiving cART containing NRTIs6NNRTIs, with at most 1 sequence selected from each therapy line of a patient. The robustness of the network was assessed with a non-parametric bootstrap using 100 replicates.…”

Clinical Management of HIV Drug Resistance

“…TAMs excision may be reduced by M184V. In addition, M184V-containing virus is less fit than wild type virus [90,91], perhaps providing an additional virologic benefit. Accumulation of TAMS results in increasing resistance to AZT, tenofovir, D4T, abacavir, and ddI.…”