Selection by AZT and rapid replacement in the absence of drugs of HIV type1 resistant to multiple nucleoside analogs

We studied the intrahost evolution and dynamics of a multidrug-resistant HI V-1, which contains an insertion of two amino acids (aa) and several aa cha nges within the reverse transcriptase (RT) gene. From an individual receivi ng intermittent therapy, sequences of 231 full-length molecular clones of H IV-1 RT were obtained from serum-derived viruses at 12 consecutive time poi nts over a period of 6 years, 17 to 20 clones per time point. In the 3.5-ye ar period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monoth erapy, all viruses contained an insertion of two aa between positions 68 an d 69 of the RT and aa changes at positions 67 and 215, a combination confer ring resistance to multiple nucleoside analogs. After termination of therap y, the insertion mutants were rapidly and completely replaced by the wt vir uses. In turn, the insertion mutants replaced the wt viruses after initiati on of therapy with 3TC, d4T, and saquinavir. After termination of triple th erapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of A ZT-resistant viruses. Fast replacements of the mutant virus populations aft er termination of therapy indicate gross competitive disadvantage of the in sertion mutant in the absence of therapy, which we estimated by using sever al models. The insertion mutants attained high virus loads, demonstrating t hat virus load cannot be used as a direct measure of virus fitness.