Bottleneck Transmission of Nucleoside Analogue-resistant HIV-1 and the Establishment of new HIV-1 RT Wild Types

Jaap Goudsmit

Substantial reductions in mortality and morbidity among HIV-1 infected individuals are the result of widespread use of combination antiretroviral therapies. Among participants of the prospective Amsterdam Cohort Studies in homosexual men, the mortality rate dropped from 15% in 1994 to 1% in 1998, while coverage by therapy combining reverse transcriptase (RT) and protease inhibitors rose from 4% to 64%. Maintenance of this success requires that viruses in the drug-naïve seropositive population remain therapy sensitive. We therefore analyzed the RT and protease genes of viruses present at the point of seroconversion of people newly infected in the period 1990-1998. Three of 43 individuals tested (7%) harbored viruses with AZT-resistant conferring mutations, all of which were replaced by AZT-sensitive virus within a year after seroconversion. The build-up of AZT-resistance is described by a mathematical model that takes into account the coverage of drug regimes selecting AZT-resistance, the lag time in which resistance is gained and lost, the death rate of people infected with resistant virus, and the replacement of resistance-selecting regimes by more potent treatments that substantially reduce viral load. Our model indicates that the frequency of resistance in a population is determined largely by the number of individuals on insufficient or failing therapy and only modestly influenced by secondary transmission of AZT-resistant strains. However, viruses with a variant RT arise rapidly in most, if not all individuals infected with a 215Y AZT-resistant virus. These RT variants with improved fitness contain a D, S or N at position 215 and are shown to be equally fit in vitro to 215T mutants. Such AZT-sensitive mutants are only one mutational step removed from the 215Y mutation and evidence is obtained in the Amsterdam Cohort Studies for the first transmission of a 215D mutant that was shown to be stable during follow-up. These data point to the establishment of new transmissible and drug-sensitive HIV-1 wild types due to transmission of nucleoside analogue-resistant virus.

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