Independent evolution of the env and pol genes of HIV-1 during zidovudine therapy

Abstract

Objective: To determine the effect that selection for antiviral resistance in the HIV-1 pol gene has on the level of variation and pattern of evolution in the V3 region of env.

Design: Proviral genomes obtained from two patients before, during and after the termination of zidovudine (ZDV) therapy (approximately 2 years) were amplified and sequenced in pol and env, and the evolution of the V3 hypervariable region compared with that of the reverse transcriptase domain of pol.

Methods: Gene fragments were polymerase chain reaction-amplified from patients' peripheral blood mononuclear cells. Nucleotide sequencing was carried out using T7 DNA polymerase and dye-labelled terminators on an automated DNA sequencer. Sequences were analysed using maximum likelihood phylogenetic techniques.

Results: Both patients showed multiple resistance-associated mutations after 1 year of ZDV therapy. Sequence diversity in V3 showed no reduction during the period of treatment. Substantial change continued to occur in this region and multiple lineages were present in both patients, in contrast to the single lineage observed in the pol gene of one (patient 74), a difference confirmed by likelihood ratio tests.

Conclusions: There is no evidence from this study that selection due to antivirals has any significant impact on the evolution of the env gene. The independence in the evolution of these genes implies that recombination was occurring between the two genes during the study period. Such independent evolution should be allowed for in developing strategies for HIV therapy involving multiple target genes.