Molecular evidence for drug-induced compartmentalization of HIV-1 quasispecies in a patient with periodic changes to HAART

Objective: To perform molecular analysis of the predominant viral populatio ns and drug-resistance mutations from plasma and peripheral blood mononucle ar cell (PBMC) compartments over time from an HIV infected patient, who exp erienced virological failure while on different HAART regimens. Materials and methods: In a longitudinal study proviral and plasma HIV-1 se quences were amplified in the pol, protease and env genes and were sequence d directly and analysed phylogenetically. Virus was recovered from time poi nts corresponding to viral load peaks using co-culturing techniques. The pe riodic failure of different highly active antiretroviral therapy (HAART) re gimens was analysed sequencing. Results: Longitudinal follow-up studies revealed four inflection peaks of p lasma viraemia associated with the recovery of culturable virus in vitro, w hich indicated failure of the concurrent HAART regimen. Molecular analysis of viral strains revealed evidence of continual evolution and compartmental ization of drug-resistance mutants/quasispecies between plasma and PBMC, wi th the widest spectrum of mutations isolated from plasma. Importantly, thes e data show the periodic appearance and clearance of drug-resistance mutant s concomitant with the introduction and withdrawal of zidovudine over time. Conclusion: This report is unique in showing drug-induced compartmentalizat ion of viral quasispecies under the control of different HAART regimens in both plasma and PBMC. Introduction and withdrawal of zidovudine from the HA ART regimen had direct bearing on the appearance and disappearance of speci fic zidovudine drug-resistance mutations in plasma-derived virus. This data has important implications for the management of HIV-infected patients wit h poor compliance with certain HAART regimens, and also in predicting the l ate emergence of drug-resistance mutations via the latent integrated provir us. (C) 2000 Lippincott Williams & Wilkins.