Anti-HIV, anti-inflammatory and safety profile of the PDB microbicide candidate (HUM8P.342)

Abstract

Abstract Topical microbicides (vaginal gels) are one mechanism to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1). We show here that a new class of microbicides, abasic phosphorothioate 2’ deoxyribose backbone (PDB) oligomers, has significant anti-HIV-1 activities in human PBMC cell cultures when either the virus or cells are pre-incubated with the compound. HIV infection is also inhibited in an explant model of human cervical tissue. A second function of PDB other than its anti-HIV activity is its capacity to inhibit HIV-triggered TLR7/9 activation. PDB suppresses the release of HIV-induced pro-inflammatory cytokines/chemokines in cultures of human PBMC and ectocervical tissues. We also demonstrated that PDB is safe and non-toxic in in vitro cell cultures and in an in vivo murine vaginal toxicity model. The effect of PDB is stable as this compound retains activity at pH 4.4 and after transition to a neutral pH, following incubation with biological fluids (seminal plasma, vaginal fluids) and a normal vaginal flora Lactobacillus strain. PDB does not affect the growth of Lactobacillus strains. Phosphorothioate 2’ deoxyribose oligomers are novel microbicide candidates with dual-acting anti-HIV and anti-inflammatory activities and an excellent safety and stability profile.