Efficacy and Toxicity of Zinc Salts as Candidate Topical Microbicides against Vaginal Herpes Simplex Virus Type 2 Infection

Abstract

Zinc salt solutions administered as topical microbicides provided significant protection against herpes simplex virus type 2 infection in a mouse vaginal challenge model. However, at the therapeutic concentration, the salt solutions caused sloughing of sheets of vaginal epithelial cells. These observations limit the utility of zinc salts as microbicides and suggest that the application of zinc solutions to mucosal surfaces has the potential to cause damage that might increase susceptibility to secondary infections at a later time.

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

“…Since the vehicle (carrageenan) showed no negative effect on the architecture of the epithelia, we hypothesize that zinc may be responsible for the subtle, transient changes in the epithelia. As mentioned before, Bourne et al (7) suggested that the protection from HSV-2 infection seen in mice treated with solutions of zinc salt might be the result of epithelial sloughing and the subsequent lack of a site for primary replication of the virus. In our assay, we used highly stringent conditions: medroxyprogesterone acetate to thin the epithelia and an extremely high virus concentration (10 6 PFU/ mouse, equivalent to ϳ10,000 LD 50 s).…”

“…Perhaps this is why we saw a decrease in viability and a drop in TEER values at the 4-and 6-h time points in those formulations containing zinc and is also the primary reason that our efficacy and safety studies have focused on the in vivo model; here, the dose that was formulated in carrageenan was highly efficacious in blocking HSV-2 infection, without severe signs of toxicity. Other experiments have shown that the efficacy of zinc salts as candidate topical microbicides in the vaginal HSV-2 model could be related to the sloughing of infected epithelial cells before the virus could enter peripheral neurons (7). In this cited study, a 200 mM dose of different zinc salts (including zinc acetate) was used.…”

“…While there have been some concerns raised about adverse effects of zinc salts (used nasally in humans [3] or vaginally in mice [7]), it is important to point out that these problems have been encountered only with high doses of zinc salts (ϳ222 mM nasally and 200 mM vaginally). No zinc toxicity was seen in rabbits after daily vaginal dosing with 90 mM zinc acetate for 10 days (14) or after a 10-day treatment with zinc sulfate-loaded sponges (9).…”

“…Studies have shown that zinc salts have antiviral activity against a broad range of viruses, including HIV and HSV (4,7,19,20,27,29,45,54). Thus, topical application of formulations containing low-dose zinc salts represents a novel strategy for preventing the sexual transmission of HSV-2 and potentially HIV without the use of antiretroviral drugs.…”

A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

“…Stock titers were redetermined using the 174xCEM cell line (NIH AIDS Research & Reference Reagent Program), and the 50% tissue culture infective dose (TCID 50 ) was calculated using the Reed and Muench formula. The virus was stored at Ϫ80°C.…”