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Journal article
Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures
Antimicrobial agents and chemotherapy, v 58(12), pp 7056-7071
12 Nov 2014
PMCID: PMC4249537
PMID: 25224013
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
In the absence of universally available antiretroviral (ARV) drugs or a vaccine against HIV-1, microbicides may offer the most immediate hope for controlling the AIDS pandemic. The most advanced and clinically effective microbicides are based on ARV agents that interfere with the earliest stages of HIV-1 replication. Our objective was to identify and characterize novel ARV-like inhibitors, as well as demonstrate their efficacy at blocking HIV-1 transmission. Abasic phosphorothioate 2′ deoxyribose backbone (PDB) oligomers were evaluated in a variety of mechanistic assays and for their ability to inhibit HIV-1 infection and virus transmission through primary human cervical mucosa. Cellular and biochemical assays were used to elucidate the antiviral mechanisms of action of PDB oligomers against both lab-adapted and primary CCR5- and CXCR4-utilizing HIV-1 strains, including a multidrug-resistant isolate. A polarized cervical organ culture was used to test the ability of PDB compounds to block HIV-1 transmission to primary immune cell populations across ectocervical tissue. The antiviral activity and mechanisms of action of PDB-based compounds were dependent on oligomer size, with smaller molecules preventing reverse transcription and larger oligomers blocking viral entry. Importantly, irrespective of molecular size, PDBs potently inhibited virus infection and transmission within genital tissue samples. Furthermore, the PDB inhibitors exhibited excellent toxicity and stability profiles and were found to be safe for vaginal application in vivo. These results, coupled with the previously reported intrinsic anti-inflammatory properties of PDBs, support further investigations in the development of PDB-based topical microbicides for preventing the global spread of HIV-1.
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Details
- Title
- Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures
- Creators
- Joseph A Fraietta - Drexel UniversityYvonne M Mueller - Drexel UniversityKarissa L Lozenski - Drexel UniversityDeena Ratner - University of PittsburghAlina C Boesteanu - Drexel UniversityAidan S Hancock - Drexel UniversityCarol Lackman-Smith - Southern Research InstituteIsaac J Zentner - Drexel UniversityIrwin M Chaiken - Drexel UniversitySuhman Chung - National Institutes of HealthStuart F. J LeGrice - HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USABeth A Snyder - Southern Research InstituteMarie K Mankowski - Southern Research InstituteNatalie M Jones - Southern Research InstituteJennifer L Hope - Drexel UniversityPhalguni Gupta - University of PittsburghSharon H Anderson - Main Line FertilityBrian Wigdahl - Drexel UniversityPeter D Katsikis - Drexel University
- Publication Details
- Antimicrobial agents and chemotherapy, v 58(12), pp 7056-7071
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Microbiology and Immunology; Biology; Obstetrics and Gynecology
- Web of Science ID
- WOS:000345221000005
- Scopus ID
- 2-s2.0-84912096016
- Other Identifier
- 991019169692604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy