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Báo cáo y học: " In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy"

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: In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy. | Applegate et al. Retrovirology 2010 7 83 http www.retrovirology.eom content 7 1 83 RETR0VIR0L0GY RESEARCH Open Access In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy 1.2 13 14 1.5 Tanya Lynn Applegate Donald John Birkett Glen John Mcintyre Angel Belisario Jaramillo Geoff Symonds1 6 John Michael Murray7 2 Abstract Background Gene therapy has the potential to counter problems that still hamper standard HIV antiretroviral therapy such as toxicity patient adherence and the development of resistance. RNA interference can suppress HIV replication as a gene therapeutic via expressed short hairpin RNAs shRNAs . It is now clear that multiple shRNAs will likely be required to suppress infection and prevent the emergence of resistant virus. Results We have developed the first biologically relevant stochastic model in which multiple shRNAs are introduced into CD34 hematopoietic stem cells. This model has been used to track the production of genecontaining CD4 T cells the degree of HIV infection and the development of HIV resistance in lymphoid tissue for 13 years. In this model we found that at least four active shRNAs were required to suppress HIV infection replication effectively and prevent the development of resistance. The inhibition of incoming virus was shown to be critical for effective treatment. The low potential for resistance development that we found is largely due to a pool of replicating wild-type HIV that is maintained in non-gene containing CD4 T cells. This wild-type HIV effectively out-competes emerging viral strains maintaining the viral status quo. Conclusions The presence of a group of cells that lack the gene therapeutic and is available for infection by wildtype virus appears to mitigate the development of resistance observed with systemic antiretroviral therapy. Introduction Human Immunodeficiency Virus type 1 HIV-1 is a positive strand RNA retrovirus that can .