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

Abstract

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-1 Ba-L and simian immunodeficiency virus mac251 (SIV mac251 ). 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 (IC 50 ) of <1 M 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.

Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures

“…This feature would perhaps assist in preventing the early amplification of HIV-1 infection within mucosal membranes. Indeed, we investigated the anti-inflammatory capacities of these compounds in the context of HIV-1 infection (21), and our results are in agreement with the previously reported TLR7/9-specific antagonistic properties of deoxyribose phosphorothioates (22)(23)(24). However, the direct antiviral mechanisms of action of PDBs against HIV-1 are unknown.…”

“…PDB 14 is a potent inhibitor of HIV-1 infection (21). Based on these observations, we postulated that different lengths of PDB may exhibit various degrees of inhibitory activity.…”

“…Importantly, PDBs also block Toll-like receptor 7/9 (TLR7/9) activation and are thus capable of suppressing innate immune responses triggered by virus-specific molecules (21). This feature would perhaps assist in preventing the early amplification of HIV-1 infection within mucosal membranes.…”

“…We recently demonstrated that phosphorothioate 2= deoxyribose backbone (PDB) oligomers are nontoxic, stable, and potent inhibitors of HIV-1 and simian immunodeficiency virus (SIV) infections (21). Importantly, PDBs also block Toll-like receptor 7/9 (TLR7/9) activation and are thus capable of suppressing innate immune responses triggered by virus-specific molecules (21).…”

Azasugar-Containing Phosphorothioate Oligonucleotide (AZPSON) DBM-2198 Inhibits Human Immunodeficiency Virus Type 1 (HIV-1) Replication by Blocking HIV-1 gp120 without Affecting the V3 Region

“…Another study showed that P = S ONs interact with a peptide derived from the N-terminal heptad repeat region of gp41, blocking gp41 sixhelix bundle formation (Vaillant et al, 2006). Recently, a short 14-mer P = S 2′ deoxyribose backbone was demonstrated to enhance anti-HIV-1 activity by blocking Toll-like receptor 7 (TLR7) and TLR9, thus inhibiting the initial spread of HIV-1 after infection (Fraietta et al, 2010).…”