Table of Contents
I. Introduction
II. Herpes as a common sexually transmitted infection
III. Current treatment for herpes
IV. Need for new anti-HSV agents
V. Clinical trials for herpes vaccine development
VI. Microbicides as alternative strategy
• Categorization of microbicides against HSV
• RNAi-based microbicides
• Anionic polymers for preventing viral entry
• Molecules that block transmission at the mucosal surface
VII. Oximacro as an attractive candidate for the development of novel microbicides
VIII. Conclusion
Herpes is a super-common infection that stays in the body for life with genital herpes infection becoming one of the world’s most prevalent sexually transmitted infections. Sexually transmitted infections (STIs) are a major cause of morbidity and mortality worldwide. WHO and partners are working to accelerate research to develop new strategies for prevention and control of genital and neonatal HSV-1 and HSV-2 infections. The standard treatment of symptomatic primary or recurrent HSV infections relies on nucleoside analogues targeting viral DNA polymerase. However, there is no cure as none of them can eliminate an established latent infection. Also the main problem is for immunocompromised patients as the prolonged drug usage might lead to treatment failures due to the development of antiviral-resistant virus strains. The limitations of the available drugs for herpes and the lack of efficacious vaccines to prevent HSV infections demands more investigation. Hence there is a need for the development of new anti-HSV agents.
Recently, a clinical trial using an adenovirus serotype 5 (Ad5) vector, the STEP trial sponsored by Merck & Co Inc, was stopped because the prevention of HIV-1 infection was not observed, despite the induction of HIV-specific CD8+ T-cells. Similarly, another vaccine trial, which combined two vaccines that had performed poorly when administered individually (ALVAC HIV, a recombinant canarypox vector vaccine, combined with AIDSVAX [Global Solutions for Infectious Diseases], a glycoprotein 120 subunit vaccine; NCT00223080), reported only modest protection from HIV-1 infection (31% fewer infections in the vaccinated group compared with the placebo-treated group). As, HSV-2 can facilitate HIV-1 transmission alternative strategies are required to prevent transmission of these diseases. Subunit vaccines developed for HSV-2 have demonstrated limited efficacy, probably as a result of the inability to elicit CD8+ T-cells. Live, replication-defective HSV-2 is currently being evaluated as a candidate HSV-2 vaccine.
One alternative strategy is represented by the use of topically applied microbicides, and such agents are being developed against various viruses. Microbicides are topically applied compounds that inhibit viral transmission. Based on their mechanism of action, microbicides against HSV can be categorized into three groups. The first group includes compounds such as surfactants and detergents that directly inactivate the virus, while the second group consists of compounds that enhance the natural defense mechanisms of mucosal surfaces; compounds of both these groups are quite nonspecific and may exert a broad spectrum of antiviral activity. The third group contains molecules that impair viral attachment and/or entry into host cells and that may display a certain degree of specificity.
RNAi-based microbicides have recently been demonstrated to prevent HSV-2 transmission. RNAi is a mechanism used by many species to regulate RNA expression. It has been observed that injection of small stretches of dsRNA resulted in cleavage of homologous target mRNA and this pathway was also identified in mammalian cells. Gene silencing via the RNAi pathway is mediated by small non-coding RNAs, 21 to 25 nucleotides in length, termed siRNAs. Because of their specificity and potency, siRNAs have attracted significant attention as potential therapeutic agents. Topical application of siRNAs targeting HSV-2 viral genes protected mice from lethal HSV-2 challenge. siRNAs targeting the essential HSV-2 genes encoding for UL27, the viral envelope glycoprotein B, and UL29, a DNA-binding protein, were complexed with a cationic lipid transfection reagent. The complex was applied to vaginal mucosa, both prior to and following challenge with a lethal dose of HSV-2. siRNAs targeting viral genes, conferred up to 80% protection from infection. The complexed siRNAs did not cause overt inflammation or toxicity. Anionic polymers also prevent viral binding or entry into host cells. PRO-2000 (Endo Pharmaceuticals Solutions Inc), a naphthalene sulfonate polymer antimicrobial gel that binds CD4. PRO-2000 and cellulose sulfate may be useful in blocking HSV-2 entry into target cells by binding glycoprotein-B. Microbicides that target specific viral proteins or host factors required for viral infection are also under development. siRNAs can induce undesirable responses, and these must be identified when using a new delivery strategy and/or siRNA sequence. The main problems encountered, such as off-target effects and activation of immune responses, can be overcome by using chemically modified siRNAs. Limiting siRNA delivery to specific cell types should also minimize unwanted responses.
Molecules that block transmission at the mucosal surface can also provide a realistic method of prophylactic intervention. In a study published by Gribaudo et al in 2016 proposed use of Oximacro(®) as an attractive candidate for the development of novel microbicides of natural origin for the prevention of HSV infections. In the absence of efficient preventive vaccines, topical microbicides offer an attractive alternative in the prevention of Herpes simplex type 1 (HSV-1) and type 2 (HSV-2) infections. Because of their recognized anti-adhesive activity against bacterial pathogens, cranberry (Vaccinium macrocarpon Ait.) extracts may represent a natural source of new antiviral microbicides. They also reported novel cranberry extract Oximacro(®) and its purified A-type proanthocyanidins (PACs-A) inhibits HSV-1 and HSV-2 replication in vitro. They revealed that in the mode of action Oximacro(®) prevents adsorption of HSV-1 and HSV-2 to target cells. Further with the mechanistic studies they confirmed that Oximacro(®) and its PACs-A target the viral envelope glycoproteins gD and gB, thus resulting in the loss of infectivity of HSV particles. Moreover, Oximacro(®) completely retained its anti-HSV activity even at acidic pHs (3.0 and 4.0) and in the presence of 10% human serum proteins; conditions that mimic the physiological properties of the vagina – a potential therapeutic location for Oximacro(®). They showed for the first time that a cranberry extract highly enriched in A-type PACs exerts potent dose-dependent antiviral activity against clinical isolates of HSV-1 and HSV-2, the mechanism for which involves the inhibition of the initial virus attachment to the surface of target cells. Topical microbicides against genital herpes infection should be applied directly to the genital tract for protection. For this reason, the stability of Oximacro® was tested at various pH and in the presence of human serum proteins. The results showed that these treatments did not reduce the stability of Oximacro® to any significant degree, thus suggesting that Oximacro® is suitable for vaginal application without incurring any significant loss of antiviral activity. The anti-HSV activity of Oximacro®thus calls for further studies to be performed to evaluate its efficacy and safety in murine models of acute infection, in order to validate its development as a novel candidate microbicide of natural origin for the prevention of HSV infections.