Discovery of Novel Ribonucleoside Analogs with Activity against Human Immunodeficiency Virus Type 1
| Autor: | Laurent Bonnac, Michael J. Dapp, Steven E. Patterson, Louis M. Mansky |
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| Rok vydání: | 2014 |
| Předmět: |
Transcription
Genetic Anti-HIV Agents Immunology Biology Virus Replication Polymerase Chain Reaction Microbiology Retrovirus Transcription (biology) Virology Vaccines and Antiviral Agents Humans APOBEC3G DNA Primers Genetics Base Sequence Reverse Transcription Process Ribonucleoside biology.organism_classification Reverse transcriptase HEK293 Cells Viral replication Insect Science HIV-1 Ribonucleosides SAMHD1 |
| Zdroj: | Journal of Virology. 88:354-363 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Reverse transcription is an important early step in retrovirus replication and is a key point targeted by evolutionarily conserved host restriction factors (e.g., APOBEC3G, SamHD1). Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a major target of antiretroviral drugs, and concerns regarding drug resistance and off-target effects have led to continued efforts for identifying novel approaches to targeting HIV-1 RT. Several observations, including those obtained from monocyte-derived macrophages, have argued that ribonucleotides and their analogs can, intriguingly, impact reverse transcription. For example, we have previously demonstrated that 5-azacytidine has its greatest antiviral potency during reverse transcription by enhancement of G-to-C transversion mutations. In the study described here, we investigated a panel of ribonucleoside analogs for their ability to affect HIV-1 replication during the reverse transcription process. We discovered five ribonucleosides—8-azaadenosine, formycin A, 3-deazauridine, 5-fluorocytidine, and 2′- C -methylcytidine—that possess anti-HIV-1 activity, and one of these (i.e., 3-deazauridine) has a primary antiviral mechanism that involves increased HIV-1 mutational loads, while quantitative PCR analysis determined that the others resulted in premature chain termination. Taken together, our findings provide the first demonstration of a series of ribonucleoside analogs that can target HIV-1 reverse transcription with primary antiretroviral mechanisms that include premature termination of viral DNA synthesis or enhanced viral mutagenesis. |
| Databáze: | OpenAIRE |
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