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Background:  Infection with resistant HIV-1 may affect antiretroviral therapy success, and persistence of such strains can result in further transmission. We studied evolution of HIV-1 reverse transcriptase (RT) conferring resistant mutations after transmission.

Methods:  Recent HIV-1 infections were prospectively identified within the Amsterdam Cohort Studies. Sequences of RT and protease were obtained by population-based nucleotide sequence analysis of the HIV pol gene at the first HIV RNA sample. Major drug resistant mutations were identified based on the IAS-USA resistance table. Longitudinal samples were sequenced for those infected with a resistant strain.

Results:  Seven seroconverters, infected with a strain conferring mutation resistant to NRTI, were eligible for this study. All these mutations (combinations at RT of:  41L, 67N, 70R, 210W, 215Y/F, 219Q) persisted through follow-up, only the 215Y/F mutant changed to 215L/S/N/D. Elsewhere on the RT amino acid substitutions were observed during follow-up, but none were common among the participants. The person with the longest untreated follow-up was infected with a strain with the mutations 41L and 215Y, that mutated to 215N, and later to 215D: after 7.5 years the mutations 41L and 215D still persisted. One person stopped therapy after 4 years of treatment and the resistant strain returned as identified during the year before the start of treatment (41L and 215D). A person failing on therapy was initially infected with the mutations 41L, 210W, and 215Y. During 3 years of follow-up prior to the start of treatment these 3 mutations persisted as the main strain, except that 215Y was replaced by a 215D and 4 other amino acid changes took place at RT. After 4 months of treatment, a sample was sequenced in which 215D was replaced by the resistant 215Y. Yet this was not an outgrowth of the archived virus that initially infected this person. Since the last sequence before treatment was identical to the strain present at treatment except at amino acid position 215, we concluded that amino acid Y at position 215 had evolved from amino acid D. After 8 years on a range of therapies resistant mutations accumulated at both RT and protease.

Conclusions:  Resistant HIV strains have formed new transmissible HIV variants. Through accumulation of mutations novel pathways on the fitness landscape are explored. When failing on therapy high plasma viral load will be retained and resistance to more drug-classes evolves.

Keywords: evolution; resistance; mutations