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Abstract
VIRAL INFECTIVITY, REPLICATION, AND QUASISPECIES EVOLUTION OF HIV-1 IN PRIMARY INFECTION
PETRELLA M, BRENNER B, SPIRA B, ROUTY J, WAINBERG M
Background: Published findings show that drug resistance mutations impair the fitness of HIV-1 to varying degrees. In this study, we are continuing research to evaluate the relative replicative competence of dual and triple class multidrug resistant viruses acquired during primary HIV infection.
Methods: Sequential genotypic and phenotypic resistance testing was performed on plasma samples from untreated PHI patients with MDR during a 12-month follow-up period. Where available, virus from identified source partners was also profiled. In addition, PBMCs from PHI patients and their source partners were cultured at specified times to generate viral stocks. Viral infectivity (TCID50), p24 antigen and reverse transcriptase (RT) levels were ascertained and correlated with the genotypic and phenotypic resistance profiles. Expanded MDR and WT viral stocks were observed to be genotypically stable for >6 months. These stocks were used to conduct competitive fitness assays with varying proportions of matched MDR and WT viruses.
Results: In general, we observed a marked impairment of viral infectivity and replicative capacity of MDR viruses harboring 8-18 resistance mutations until the disappearance of key resistance-conferring mutations. In particular, high-titer viral stocks were not obtained until reversion of the 184V mutation associated with 3TC resistance from the MDR backbone. At initially equivalent titer and p24 levels, genotypically stable MDR variants show 10 to 30-fold diminished replicative capacity relative to WT virus, as measured by RT levels. Competitive fitness assays confirmed a marked replicative disadvantage of MDR variants compared to matched WT viruses. MDR and WT co-infections can lead to the expansion de novo intermediate quasispecies absent in WT or MDR viral cultures.
Conclusions: It is intriguing and worthy of further study to understand how replicatively incompetent MDR viruses establish persistent infection capable of generating high viremia
The 1st. IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
143
Suggested Citation
"PETRELLAM, et al.
VIRAL INFECTIVITY, REPLICATION, AND QUASISPECIES EVOLUTION OF HIV-1 IN PRIMARY INFECTION.
Oral Presentation:
The 1st. IAS Conference on HIV Pathogenesis and Treatment
:
Abstract no.
143"
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