tailieunhanh - Báo cáo y học: "Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học 'Respiratory Research cung cấp cho các bạn kiến thức về ngành y đề tài:"Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs. | Schopman et al. Retrovirology 2010 7 52 http content 7 1 52 gtr RETROVIROLOGY RESEARCH Open Access Anticipating and blocking HIV-1 escape by second generation antiviral shRNAs Nick CT Schopman Olivier ter Brake and Ben Berkhout Abstract Background RNA interference RNAi is an evolutionary conserved gene silencing mechanism that mediates the sequence-specific breakdown of target mRNAs. RNAi can be used to inhibit HIV-1 replication by targeting the viral RNA genome. However the error-prone replication machinery of HIV-1 can generate RNAi-resistant variants with specific mutations in the target sequence. For durable inhibition of HIV-1 replication the emergence of such escape viruses must be controlled. Here we present a strategy that anticipates HIV-1 escape by designing 2nd generation short hairpin RNAs shRNAs that form a complete match with the viral escape sequences. Results To block the two favorite viral escape routes observed when the HIV-1 integrase gene sequence is targeted the original shRNA inhibitor was combined with two 2nd generation shRNAs in a single lentiviral expression vector. We demonstrate in long-term viral challenge experiments that the two dominant viral escape routes were effectively blocked. Eventually virus breakthrough did however occur but HIV-1 evolution was skewed and forced to use new escape routes. Conclusion These results demonstrate the power of the 2nd generation RNAi concept. Popular viral escape routes are blocked by the 2nd generation RNAi strategy. As a consequence viral evolution was skewed leading to new escape routes. These results are of importance for a deeper understanding of HIV-1 evolution under RNAi pressure. Background Worldwide more than 30 million individuals are infected with human immunodeficiency virus type 1 HIV-1 and each year approximately 3 million persons become newly infected. Treatment options have improved dramatically with the introduction of highly active antiretroviral therapy HAART

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