Herpes viruses are important human pathogens, causing both primary and secondary infections that range from trivial mucosal ulcers to life threatening disorders in immuno-compromised patients 12. The Herpes group includes HSV-1, HSV-2, Herpes Zoster (chicken pox/shingles), HCMV (human cytomegalovirus), EBV, Herpes 6, 7 (Roseola, post transplant infections) and Herpes 8 (associated with Kaposi sarcoma). The conventional treatment of these infections is with drugs such as acyclovir (ACV) that target the viral DNA polymerase. Whilst these drugs are undoubtedly efficient, their long-term use has led to the development of resistant viral strains that now comprise 5% of all HSV infections in immuno-compromised patients 1. Finding non-toxic alternatives to these drugs is of interest to patients and to drug companies investigating more effective remedies. Whilst the epidemiology and serotype of Herpes infections varies widely within the world community, as a result of differing subpopulations and childhood exposure rates, it seems that the incidence of HSV2 in Japanese women is substantially less than that of American women. (e.g., 50% seroprevalence in one study of African-American women vs. 7% in Japan) 3. We also noted that the reactivation of Herpes simplex I (HSV-1) as measured by shedding 4 is considerably less in the Japanese population than in the west. However, EBV, some strains of which are associated with malignancies, affects over 90% of the population world wide 5, and seropositivity for CMV is higher in the Japanese population 6.

Several plants have been shown to have anti-viral activity, but edible brown marine algae are unique in that they are a regular part of the Japanese daily diet. Key anti-viral active agents within brown algae are the sulphated polyanions 789. In recent years both natural and synthetic sulphated polyanions have been a research focus for their potential therapeutic activity. They are considered to act principally by inhibiting the entry of coated viruses such as Herpes into host cells 789, by competing for receptors at the cell surface. This activity is, in part, due to the similarities of the algal polyanions to mammalian heparin sulphate molecules. There are a number of receptors (including a heparin sulphate receptor) expressed differentially on various cell types, which provide entry points for Herpes viruses 10. This mechanism of inhibition contrasts with that of commonly used drugs such as ACV which act as nucleic acid inhibitors, preventing viral replication after the virus has entered the cell.

The main seaweed in the Japanese daily diet is Undaria pinnatifida, commonly known as 'wakame' 11. The major sulphated polyanion present in Undaria is characterised as a 'galactofucan sulphate' 1213. Other sulphated polyanions such as the synthetic dextran sulphates, pentosan sulphates, clinically used heparins, and seaweed-derived carageenans have all been investigated for anti-viral activity in humans, either systemically or topically 789. However, to date, Undaria ingestion has not been clinically assessed in a western population for its effects on common coated viruses such as HSV-1 and 2 which have reduced incidence in the Japanese population 34. Undaria extracts have been shown to have anti-viral effects on HSV-1 in vitro 14 and also against the Herpes group virus Epstein Barr Virus or EBV 15. Specific molecules were not identified in these studies, thus the observed anti-viral activity may arise from either or both polyanions and other components. Undaria aqueous extract (made by boiling Undaria in water) and a partially purified galactofucan sulphate extract were recently assessed for activity against clinical isolates of Herpes I and Herpes II in vitro 1617. Twenty of the viral strains were sensitive to ACV, and nineteen were resistant. In the test, both types of extract were active against all strains, and more active against strains of HSV-2 than strains of HSV-1. The mode of action was shown to be blocking attachment and entry of HSV into the host cells.

Undaria fractions have also been shown to have immune stimulating qualities in vitro 18 and other brown seaweed fractions have been shown to have immunological effects in vivo 1989.

The mechanism of viral inhibition by polyanions such as galactofucan does not generate resistant strains at the same rates as ACV 7. Aside from the inhibition of viral infectivity, it is possible that immune stimulation via polyanions or other components, increases anti-viral activity 1819

We hypothesised that Undaria ingestion may be associated with resolution of Herpes infections in a western population, and that this would be reflected by inhibition of HSV infectivity and increased T cell activity in vitro. In this study, a proprietary Undaria preparation 'GFS' was assessed for effects on the healing of, and the inhibition of outbreaks of HSV infections in otherwise healthy patients. In addition, whole aqueous extracts of the GFS were assessed for effects on HSV infectivity in vitro and on human T cell stimulation in vitro.

This study was carried out to assess the effects of GFS in patient studies and in vitro.

GFS was ingested by patients suffering active or latent Herpes infections. Results indicated firstly, a positive effect on healing, and secondly, inhibition of outbreaks in cases of HSV-1, HSV-2, ACV resistant HSV-2, and zoster. There were no adverse side effects noted, and GFS was well tolerated by all subjects. Reduced pain levels were noted in some cases.

A particularly noteworthy result in this study was inhibition of an ACV resistant case of HSV-2. HSV-2 is a sexually transmitted disease of increasing incidence 4. In part, this is due to the fact that partner transmission may occur during asymptomatic shedding 4 or unrecognised minor outbreaks. Suppressive therapies such as ACV have been tested for their ability to inhibit shedding 20. However, for long-term use, non-toxic alternatives such as GFS may be preferred by patients, who perceive long-term conventional drug use as detrimental. In addition, GFS may reduce the generation of resistant strains which arise through prolonged use of drugs such as ACV.

GFS extract potently inhibited HSV and HCMV infection of human cells, and stimulated human T cell proliferation in vitro. In other studies 1617 extracts were active against clinical strains of HSV. These mechanisms may be relevant to the observed clinical response.

Human T cell proliferation in vitro observed here concurs with observations by Shan et al 18. Shan found that in the presence of various seaweed extracts including Undaria, lymphocyte proliferation and cytotoxic T cell activity was enhanced, but that NK cell activity was not. Cytotoxic T cells play a prominent role in the immune response in the local environment of HSV-2 infections 21, and have been shown to be key elements of immune defence against HSV-I and other viruses 2223. Thus the observed T cell mitogenic effect caused by GFS in vitro may be related to enhanced immunity in vivo.

Sulphated molecules with similarities to sulphated galactofucan, such as dermatan sulphate have been shown to be present in plasma after oral ingestion 24. Macromolecules are known to pass through the gut into plasma and into lymph via the extensive gut lymphoid system 25 where they may affect immune function. The gut lymphoid system or 'GALT' comprises Peyers patches and gut cryptopatches where different types of T cells and other immune cells participate in uptake or contact with gut contents. T cell uptake or contact with GFS by either Peyers patch or gut cryptopatch dwelling cells may result in the proliferative response noted here in vitro. However, immune indicators were not measured in this study.

Whilst further research is called for, the results obtained in this study show that ingestion of GFS is associated with resolution, reduced pain and outbreak inhibition of Herpes virus infections. Studies regarding uptake, immunostimulation and anti-viral effects of GFS are in progress.

The rise in nucleic acid inhibitor resistant strains of HSV-2, and the need for less aggressive anti-viral therapies, indicates a role for alternative therapeutic routes such as that demonstrated here for GFS.

Ingestion of GFS has inhibitory effects on reactivation of HSV and positively affects the resolution of active Herpes infections. GFS has inhibitory effects on Herpes infectivity in vitro and a T cell mitogenic effect in vitro.

The mechanism of inhibition of Herpes infections may be, in part, mediated by galactofucan present in the GFS.

Russell Cooper, Ken Thompson, John Godwin, Kate Elliot have no declared interests. JH Fitton and Charles Dragar are employed Marine Biomedical Research Tasmania Australia.

RC, JG, KE and JHF participated in clinical studies and JHF drafted the manuscript. KT carried out the in vitro studies. JHF and CD conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.