Candidate Topical Microbicides Bind Herpes Simplex Virus Glycoprotein B and Prevent Viral Entry and Cell-to-Cell Spread

Abstract

Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.

Candidate Sulfonated and Sulfated Topical Microbicides: Comparison of Anti-Human Immunodeficiency Virus Activities and Mechanisms of Action

“…T-PSS, CS, PMHS, and PRO 2000 differ from other proposed microbicides in that they are neither detergents nor surfactants and they do not appear to have cytotoxic effects on human cervical epithelial cells (4).…”

“…We observed no toxicity in a setting of either repeated exposure (2 h for 5 days) or chronic exposure (48 continuous hours) to SPs ( Table 3). The toxicities of these compounds have also been determined for human endocervical cells and were previously published (4).…”

Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

“…PPCM is not cytotoxic in vitro against cervical epithelial or immune cells (9,21) and shows no cytotoxicity when cervical or penile glans explant tissue is used. PPCM gel is not cytotoxic toward lactobacilli, is not mutagenic, has low acute oral toxicity, and is safe in the rabbit vaginal irritation assay (47).…”

A Review of Current Intravaginal Drug Delivery Approaches Employed for the Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Infections

“…Monoclonal antibodies are molecules synthesized by the immune system as 'mirror images' of foreign substances (158). A long-range goal in vaginal protection is to develop monoclonal human antibodies in a microbicidal gel for protecting genital skin and epithelia against infections by topical passive immunization.…”