3-Hydroxyphthaloyl β-Lactoglobulin. IV. Antiviral Activity in the Mouse Model of Genital Herpesvirus Infection

Abstract

The spread of sexually transmitted infections caused by herpes simplex virus type 2 (HSV-2) has continued unabated despite educational efforts generated in response to the human immunodeficiency virus (HIV) epidemic. Given the absence of effective vaccines, this indicates the need to develop prophylactic measures such as topical antiviral agents. Chemical modification of bovine β-lactoglobulin (β-LG), the major protein of whey, by hydroxyphthalic anhydride (3HP) led to the generation of a potent HIV-1 inhibitor designated 3HP-β-LG. This agent was shown to also have antiviral activity against HSV-2 and HSV-1 in vitro. Recent studies indicate that 3HP-β-LG binds to HSV-1 virions, which, at least in part, involves the viral glycoprotein gE. Here we show that 3HP-β-LG inhibits HSV-2 infection in the mouse model of genital HSV-2 infection. Simultaneous exposure to HSV-2 and 3HP-β-LG caused a significant decrease in the proportion of infected animals (27% virus shedding, 5% lesion development and 0% fatality for 3HP-β-LG as compared to 80% shedding, 60% lesion development and 53% fatality in micetreated with PBS). The proportion of animals with HSV-2 infection after treatment with β-LG was similar to that in the PBS-treated group. Pretreatment with 3HP-β-LG formulated in a gel, which prolongs the presence of the agent in the vagina, also significantly reduced the proportion of HSV-2-infected mice (5% virus shedding, 5% lesion development and 0% fatality for 3HP-β-LG as compared to 70% shedding, 60% lesion development and 40% fatality in vehicle-treated mice). These differences were significant ( P≤0.0005, 0.002 and 0.008 for shedding, lesion development and fatality, respectively). Virus titres in the minority of mice that developed infection were similar to those in untreated mice. HSV-2 infection was not inhibited by treatment of an ongoing infection, indicating that 3HP-β-LG interferes with the initial infection. These data suggest that 3HP-β-LG may be an efficacious agent for preventing vaginal transmission of genital herpesvirus infections.

Cellulose Acetate Phthalate (CAP): An ‘Inactive” Pharmaceutical Excipient with Antiviral Activity in the Mouse Model of Genital Herpesvirus Infection

“…As summarized in Tables 1 and 2, the vaginal HSV-2 model used in these experiments is reproducible, with an incidence of infection in untreated animals virtually identical to that reported before (Kokuba et al, 1998). Thus, virus was first isolated from untreated mice infected with 2×10 5 p.f.u of HSV-2 at 3 days post-infection (p.i).…”

Antiviral properties of milk proteins and peptides

“…However, the modified peptides showed a cytotoxic effect on the Vero cells. Kokuba, Aurelian, and Neurath (1998) reported that 3-HP-b-Lg prevented HSV-2 infection in the mouse model of genital HSV-2 infection, suggesting that 3-HP-b-Lg might be an efficacious agent for preventing vaginal transmission of genital herpesvirus infections. Schoen, Corver, Meijer, Wilschut, and Swart (1997) also reported that acylated milk proteins were effective against influenza virus.…”

3-Hydroxyphthalic Anhydride-Modified Chicken Ovalbumin Exhibits Potent and Broad Anti-HIV-1 Activity: a Potential Microbicide for Preventing Sexual Transmission of HIV-1

“…Our group previously discovered a series of chemically modified bovine milk proteins with anti-HIV-1 activity (46). One of the most efficient antiviral agents is 3-hydroxyphthalic anhydride-modified ß-lactoglobulin (3HP-ß-LG), which is a promising candidate microbicide to prevent the sexual transmission of HIV-1 because of its broad antiviral activity against HIV-1, HIV-2, SIV, and HSV and against Chlamydia trachomatis (25,28,33,47,49,51). Most importantly, 3HP-ß-LG is highly soluble and stable for long-term storage.…”