ArticleMolecular therapy : the journal of the American Society of Gene Therapy2012
HIV develops indirect cross-resistance to combinatorial RNAi targeting two distinct and spatially distant sites.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Protection of animals against devastating RNA viruses using CRISPR-Cas13s.Molecular therapy. Nucleic acids · 2024Article
- Ex vivo and in vivo suppression of SARS-CoV-2 with combinatorial AAV/RNAi expression vectors.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- In silico analysis suggests the RNAi-enhancing antibiotic enoxacin as a potential inhibitor of SARS-CoV-2 infection.Scientific reports · 2021Article
- CRISPR-Cas13a Inhibits HIV-1 Infection.Molecular therapy. Nucleic acids · 2020Article
- Multi-targeting of viral RNAs with synthetic trans-acting small interfering RNAs enhances plant antiviral resistance.The Plant journal : for cell and molecular biology · 2019Article
- CRISPR/Cas9 and Genome Editing for Viral Disease-Is Resistance Futile?ACS infectious diseases · 2018Review
- Review
- Efficacy Analysis of Combinatorial siRNAs against HIV Derived from One Double Hairpin RNA Precursor.Frontiers in microbiology · 2017Article
- Review
- RNA interference approaches for treatment of HIV-1 infection.Genome medicine · 2015Article
- Inhibition of hepatitis C virus in chimeric mice by short synthetic hairpin RNAs: sequence analysis of surviving virus shows added selective pressure of combination therapy.Journal of virology · 2014Article
- The impact of unprotected T cells in RNAi-based gene therapy for HIV-AIDS.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- Characteristics of HIV-1 natural drug resistance-associated mutations in former paid blood donors in Henan Province, China.PloS one · 2014Article
- Promoter Targeting shRNA Suppresses HIV-1 Infection In vivo Through Transcriptional Gene Silencing.Molecular therapy. Nucleic acids · 2013Article
- Improving the effectiveness of artificial microRNA (amiR)-mediated resistance against Turnip mosaic virus by combining two amiRs or by targeting highly conserved viral genomic regions.Journal of virology · 2013Article
- Functional in vivo delivery of multiplexed anti-HIV-1 siRNAs via a chemically synthesized aptamer with a sticky bridge.Molecular therapy : the journal of the American Society of Gene Therapy · 2013Article
- Creating genetic resistance to HIV.Current opinion in immunology · 2012Review
- Response to "HIV Escape From RNAi Antivirals: Yet Another Houdini Action?".Molecular therapy. Nucleic acids · 2012Article
- HIV-1 Escape From RNAi Antivirals: Yet Another Houdini Action?Molecular therapy. Nucleic acids · 2012Article
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Authors and funding
3 authors.
Funding
Abstract
Resistance to existing HIV therapies is an increasing problem, and alternative treatments are urgently needed. RNA interference (RNAi), an innate mechanism for sequence-specific gene silencing, can be harnessed therapeutically to treat viral infections, yet viral resistance can still emerge. Here, we demonstrate that HIV can develop indirect resistance to individual and combinatorial RNAi-targeting protein-coding regions up to 5,500 nucleotides (nt) downstream of the viral promoter. We identify several variants harboring mutations in the HIV promoter, and not within the RNAi targets, that produce more fully elongated transcripts. Furthermore, these variants are resistant to the RNAi, potentially by stoichiometrically overwhelming this cellular mechanism. Alarmingly, virus resistant to one short hairpin RNA (shRNA) also exhibits cross-resistance to a different shRNA, which targets a distinct and spatially distant region to which the virus has not been previously exposed. To our knowledge, this is the first example of HIV "cross-resistance" to viral inhibitors targeting different loci. Finally, combining anti-HIV RNAi with a small molecule enhancer of RNAi can inhibit the replication of an indirectly resistant mutant. These results suggest that indirect resistance to RNAi is a general mechanism that should be considered when investigating viral resistance and designing combinatorial RNAi therapies.
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