tailieunhanh - Báo cáo y học: " The mutation T477A in HIV-1 reverse transcriptase (RT) restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học Retrovirology cung cấp cho các bạn kiến thức về ngành y đề tài: The mutation T477A in HIV-1 reverse transcriptase (RT) restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site. | Abram et al. Retrovirology 2010 7 6 http content 7 1 6 RETR0VIR0L0GY RESEARCH Open Access The mutation T477A in HIV-1 reverse transcriptase RT restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site Michael E Abram1 Stefan G Sarafianos2 Michael A Parniak3 Abstract Background The p51 subunit of the HIV-1 reverse transcriptase RT p66 p51 heterodimer arises from proteolytic cleavage of the RT p66 subunit C-terminal ribonuclease H RNH domain during virus maturation. Our previous work showed that mutations in the RT p51fRNH cleavage site resulted in virus with defects in proteolytic processing of RT and significantly attenuated infectivity. In some cases virus fitness was restored after repeated passage of mutant viruses due to reversion of the mutated sequences to wild-type. However in one case the recovered virus retained the mutated p51fRNH cleavage site but also developed an additional mutation T477A distal to the cleavage site. In this study we have characterized in detail the impact of the T477A mutation on intravirion processing of RT. Results While the T477A mutation arose during serial passage only with the F440V mutant background introduction of this substitution into a variety of RT p51fRNH cleavage site lethal mutant backgrounds was able to restore substantial infectivity and normal RT processing to these mutants. T477A had no phenotypic effect on wildtype HIV-1. We also evaluated the impact of T477A on the kinetics of intravirion Gag-Pol polyprotein processing of p51fRNH cleavage site mutants using the protease inhibitor ritonavir. Early processing intermediates accumulated in p51fRNH cleavage site mutant viruses whereas introduction of T477A promoted the completion of processing and formation of the fully processed RT p66 p51 heterodimer. Conclusions This work highlights the extraordinary plasticity of HIV-1 in adapting to seemingly lethal mutations that prevent RT heterodimer formation

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