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Phosphorothioate 2′ Deoxyribose Oligomers as Microbicides That Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Block Toll-Like Receptor 7 (TLR7) and TLR9 Triggering by HIV-1
Journal article   Open access   Peer reviewed

Phosphorothioate 2′ Deoxyribose Oligomers as Microbicides That Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Block Toll-Like Receptor 7 (TLR7) and TLR9 Triggering by HIV-1

Joseph A Fraietta, Yvonne M Mueller, Duc H Do, Veronica M Holmes, Mary K Howett, Mark G Lewis, Alina C Boesteanu, Sefik S Alkan and Peter D Katsikis
Antimicrobial agents and chemotherapy, v 54(10), pp 4064-4073
Oct 2010
DOI: https://doi.org/10.1128/AAC.00367-10
PMID: 20625151
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1128/aac.00367-10View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Anti-Infective Agents Antiviral Agents HIV Infections Oligonucleotides Toll-Like Receptor 7 Toll-Like Receptor 9
Topical microbicides may prove to be an important strategy for preventing human immunodeficiency virus type 1 (HIV-1) transmission. We examined the safety and efficacy of sequence-nonspecific phosphorothioate 2′ deoxyribose oligomers as potential novel microbicides. A short, 13-mer poly(T) phosphorothioate oligodeoxynucleotide (OPB-T) significantly inhibited infection of primary peripheral blood mononuclear cells (PBMC) by high-titer HIV-1Ba-L and simian immunodeficiency virus mac251 (SIVmac251). Continuous exposure of human vaginal and foreskin tissue explants to OPB-T showed no toxicity. An abasic 14-mer phosphorothioate 2′ deoxyribose backbone (PDB) demonstrated enhanced anti-HIV-1 activity relative to OPB-T and other homo-oligodeoxynucleotide analogs. When PDB was used to pretreat HIV-1, PDB was effective against R5 and X4 isolates at a half-maximal inhibitory concentration (IC50) of <1 μM in both PBMC and P4-R5 MAGI cell infections. PDB also reduced HIV-1 infectivity following the binding of virus to target cells. This novel topical microbicide candidate exhibited an excellent in vitro safety profile in human PBMC and endocervical epithelial cells. PDB also retained activity in hydroxyethylcellulose gel at pH 4.4 and after transition to a neutral pH and was stable in this formulation for 30 days at room temperature. Furthermore, the compound displayed potent antiviral activity following incubation with a Lactobacillus strain derived from normal vaginal flora. Most importantly, PDB can inhibit HIV-1-induced alpha interferon production. Phosphorothioate 2′ deoxyribose oligomers may therefore be promising microbicide candidates that inhibit HIV-1 infection and also dampen the inflammation which is critical for the initial spread of the virus.

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Collaboration types
Industry collaboration
Domestic collaboration
International collaboration
Web of Science research areas
Microbiology
Pharmacology & Pharmacy
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