Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy
| Autor: | Joshua T. Schiffer, Harlan L. Pietz, Harshana S. De Silva Feelixge, Alexander L. Greninger, Daniel Stone, Pavitra Roychoudhury, Keith R. Jerome, Martine Aubert |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Anti-HIV Agents Molecular Sequence Data Gene Products pol HIV Infections medicine.disease_cause Virus Replication Virus Article Cell Line 03 medical and health sciences Endonuclease 0302 clinical medicine HIV Protease Transduction Genetic Virology Drug Resistance Viral medicine Humans Pharmacology Mutation biology Base Sequence Zinc Fingers Resistance mutation Endonucleases Phosphoproteins Zinc finger nuclease Reverse transcriptase HIV Reverse Transcriptase Integrase 030104 developmental biology Exodeoxyribonucleases HEK293 Cells Viral replication 030220 oncology & carcinogenesis DNA Viral biology.protein HIV-1 Reverse Transcriptase Inhibitors |
| Popis: | Incurable chronic viral infections are a major cause of morbidity and mortality worldwide. One potential approach to cure persistent viral infections is via the use of targeted endonucleases. Nevertheless, a potential concern for endonuclease-based antiviral therapies is the emergence of treatment resistance. Here we detect for the first time an endonuclease-resistant infectious virus that is found with high frequency after antiviral endonuclease therapy. While testing the activity of HIV pol-specific zinc finger nucleases (ZFNs) alone or in combination with three prime repair exonuclease 2 (Trex2), we identified a treatment-resistant and infectious mutant virus that was derived from a ZFN-mediated disruption of reverse transcriptase (RT). Although gene disruption of HIV protease, RT and integrase could inhibit viral replication, a chance single amino acid insertion within the thumb domain of RT produced a virus that could actively replicate. The endonuclease-resistant virus could replicate in primary CD4(+) T cells, but remained susceptible to treatment with antiretroviral RT inhibitors. When secondary ZFN-derived mutations were introduced into the mutant virus's RT or integrase domains, replication could be abolished. Our observations suggest that caution should be exercised during endonuclease-based antiviral therapies; however, combination endonuclease therapies may prevent the emergence of resistance. |
| Databáze: | OpenAIRE |
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