Title | Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Feelixge HSDe Silva, Stone D, Pietz HL, Roychoudhury P, Greninger AL, Schiffer JT, Aubert M, Jerome KR |
Journal | Antiviral Res |
Volume | 126 |
Pagination | 90-8 |
Date Published | 2016 Feb |
ISSN | 1872-9096 |
Keywords | Anti-HIV Agents, Base Sequence, Cell Line, DNA, Viral, Drug Resistance, Viral, Endonucleases, Exodeoxyribonucleases, Gene Products, pol, HEK293 Cells, HIV Infections, HIV Protease, HIV Reverse Transcriptase, HIV-1, Humans, Molecular Sequence Data, Mutation, Phosphoproteins, Reverse Transcriptase Inhibitors, Transduction, Genetic, Virus Replication, Zinc Fingers |
Abstract | 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. |
DOI | 10.1016/j.antiviral.2015.12.007 |
Alternate Journal | Antiviral Res. |
PubMed ID | 26718067 |
PubMed Central ID | PMC4724322 |
Grant List | P30 AI027757 / AI / NIAID NIH HHS / United States U19 AI096111 / AI / NIAID NIH HHS / United States U19 AI 096111 / AI / NIAID NIH HHS / United States |
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