EFFECT OF THE M184V MUTATION IN HIV REVERSE TRANSCRIPTASE (RT) ON VIRAL FITNESS IN PRIMARY INFECTION

Mark A Wainberg, Bluma Brenner, Jean-Pierre Routy, Bonnie Spira, Marco Petrella, Vidal Essebag, Brian Conway, Rafick-Pierre Sekaly
McGill University AIDS Centre, Montreal, Quebec

Background: We have examined the persistence and fitness of multidrug-resistant (MDR) viruses acquired during primary HIV infection (PHI).
Methods: Longitudinal sequence analysis was performed on plasma or PBMC samples obtained from PHI patients acquiring MDR infections. Changes in genotype and viremia over time were assessed in relation to relative viral fitness. Visible Genetics TruGene technology was used to sequence samples of viral RNA and competition replication assays in culture were used to assess fitness.
Results: Of a total of 136 subjects followed in PHI, eight presented with MDR profiles. Four of these were treated and responded to therapy while the other four, who were not treated, maintained durable MDR infections for periods between 36 weeks and 5 years. In two of these cases, a rebound to higher levels of plasma viremia only occurred when the M184V mutation in RT could no longer be detected. In a third case, detection of M184V was associated with an inability to isolate virus. In general, MDR (triple class) viral infection was associated with low levels of plasma viremia. We also studied the source partners of these four patients and observed that their viruses possessed identical MDR genotypes. In contrast, however, to these sustained MDR genotypic patterns following PHI, the viruses in the source partners reverted to wild-type genomes within 12 weeks of structured treatment interruption (STI). In dual-infection competition assays, the MDR viruses isolated from the four MDR cases demonstrated marked replicative disadvantage compared with their wild-type counterparts from the source partners, isolated after STI, as measured both by reverse transcriptase assay in culture fluids and genotyping. Reintroduction of antiretroviral drug pressure in tissue culture allowed for minor MDR variants to re-emerge, overtaking the wild-type viruses.
Conclusion: MDR viruses can establish dominant, persistent infections in PHI despite their impaired replicative competence.