Journals Excerpts of Microbicide & HPV

About HPV
Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes.

While the majority of the known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus. Recently, HPV has been linked with an increased risk of cardiovascular disease.In addition, HPV 16 and 18 infections are strongly associated with an increased odds ratio of developing orophanyngeal cancer.

More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with "high-risk" HPV types — different from the ones that cause skin warts — may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer. However, most infections with these types do not cause disease.

Microbicide & HPV
HIV-1, herpes simplex virus type 2 (HSV-2), and human papillomavirus (HPV), among other sexually transmitted infections, represent a major burden for global health. Initial insights into the mucosal transmission of these viral pathogens have raised optimism with regard to the rapid generation of protective vaccines. Nevertheless, setbacks for HIV-1 and HSV-2 vaccines have seriously challenged the initial enthusiasm.

Recently, two new vaccines that efficiently prevented HPV infection have renewed the hope that vaccinal prevention of viral mucosal sexually transmitted infections is possible. HIV-1 and HSV-2 differ from HPV, and each virus needs to be tackled with a distinct approach. However, vaccines are not the only possible answer. Topically applied agents (microbicides) are an attractive alternative in the prevention of HIV-1 and HSV-2 mucosal transmission. Progress in understanding the mechanisms of genital transmission of HIV-1 and HSV-2 is required for successful vaccine or microbicide candidates to emerge from current approaches.
(Vaccines and microbicides preventing HIV-1, HSV-2, and HPV mucosal transmission; Nikolic DS, Piguet V.)

Genital human papillomavirus (HPV) infections represent one of the most frequent sexually transmitted diseases (STDs). Although most infections spontaneously resolve within a year, most likely by host cell-mediated immunity, a proportion of persistent HPV infections can progress to invasive cervical cancer. Cervical cancer represents the second most frequent cause of cancer-related deaths in women, accounting for more than 200,000 deaths per year worldwide. Compounds with microbicidal activity against papillomaviruses, therefore, may reduce incident infections and decrease the rates of cervical cancer.

The high-molecular-weight sulfated or sulfonated polysaccharides or polymers cellulose sulfate, dextran sulfate, and polystyrene sulfonate were tested for microbicidal activity against bovine papillomavirus type 1 (BPV-1) and human papillomavirus type 11 (HPV-11) and type 40 (HPV-40). In vitro assays included the BPV-1-induced focus-forming assay and transient infection of human A431 cells with HPVs. The compounds were tested for microbicidal activity directly by preincubation with virus prior to addition to cell cultures and indirectly by addition of virus to compound-treated cells and to virus-coated cells to test inactivation of the virus after virus-cell binding.

In summary, we describe three new compounds that show microbicidal activity against BPV-1, HPV-11, and HPV-40. The mechanism of inhibition of infection appears to include both direct interaction of the compounds with infectious virions and a blocking effect at the cell surface. The lack of significant cellular toxicity of CS, DS, and PSS make these compounds attractive potential microbicides for a variety of infectious pathogens including HPV.
(Papillomavirus Microbicidal Activities of High-Molecular-Weight Cellulose Sulfate, Dextran Sulfate, and Polystyrene Sulfonate; Neil D. Christensen, Cynthia A. Reed, Tim D. Culp, Paul L. Hermonat, Mary K. Howett, Robert A. Anderson, and Lourens J. D. Zaneveld)

Certain sexually transmitted human papillomavirus (HPV) types are causally associated with the development of cervical cancer. Our recent development of high-titer HPV pseudoviruses has made it possible to perform high-throughput in vitro screens to identify HPV infection inhibitors. Comparison of a variety of compounds revealed that carrageenan, a type of sulfated polysaccharide extracted from red algae, is an extremely potent infection inhibitor for a broad range of sexually transmitted HPVs.

Although carrageenan can inhibit herpes simplex viruses and some strains of HIV in vitro, genital HPVs are about a thousand-fold more susceptible, with 50% inhibitory doses in the low ng/ml range. Carrageenan acts primarily by preventing the binding of HPV virions to cells. This finding is consistent with the fact that carrageenan resembles heparan sulfate, an HPV cell-attachment factor.

However, carrageenan is three orders of magnitude more potent than heparin, a form of cell-free heparan sulfate that has been regarded as a highly effective model HPV inhibitor. Carrageenan can also block HPV infection through a second, postattachment heparan sulfate–independent effect. Carrageenan is in widespread commercial use as a thickener in a variety of cosmetic and food products, ranging from sexual lubricants to infant feeding formulas. Some of these products block HPV infectivity in vitro, even when diluted a million-fold. Clinical trials are needed to determine whether carrageenan-based products are effective as topical microbicides against genital HPVs.
(Carrageenan Is a Potent Inhibitor of Papillomavirus Infection; Christopher B. Buck, Cynthia D. Thompson, Jeffrey N. Roberts, Martin Müller, Douglas R. Lowy, John T. Schiller)

Antibody-based technology is now coming to fruition for systemic therapeutics, but the untapped commercial applications for antibodies are in mucosal prevention. A vaginal microbicide is one important application for mucosal antibodies; antibody technology is so flexible that it is readily extended to other reproductive health applications or to the prevention of diseases by pathogens at other mucosal sites. The production of antibodies in plant as plantibodies will enable this technology to meet cost and capacity demands.
(ANTI-HPV HUMAN MONOCLONALS FOR A VAGINAL MICROBICIDE; Kevin J Whaley)