ArticleRetrovirology2010
In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy.
Article in Retrovirology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Multiplexed shRNA-miRs as a candidate for anti HIV-1 therapy: strategies, challenges, and future potential.Journal, genetic engineering & biotechnology · 2022Review
- A quantitative comparison of anti-HIV gene therapy delivered to hematopoietic stem cells versus CD4+ T cells.PLoS computational biology · 2014Article
- Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.Molecular therapy. Methods & clinical development · 2014Article
- Creating genetic resistance to HIV.Current opinion in immunology · 2012Review
- HIV develops indirect cross-resistance to combinatorial RNAi targeting two distinct and spatially distant sites.Molecular therapy : the journal of the American Society of Gene Therapy · 2012Article
- Antiviral RNAi: translating science towards therapeutic success.Pharmaceutical research · 2011Review
- A comparison of multiple shRNA expression methods for combinatorial RNAi.Genetic vaccines and therapy · 2011Article
- Ex vivo gene therapy for HIV-1 treatment.Human molecular genetics · 2011Review
- Multiple shRNA combinations for near-complete coverage of all HIV-1 strains.AIDS research and therapy · 2011Article
- MicroRNAs and human retroviruses.Biochimica et biophysica actaReview
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGene 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.
resultsWe 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 gene-containing 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.
conclusionsThe presence of a group of cells that lack the gene therapeutic and is available for infection by wild-type virus appears to mitigate the development of resistance observed with systemic antiretroviral therapy.
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