Papillomaviruses

Papillomaviruses have proven difficult to treat because of the paucity of targets in the latent phase. Thus, treatment regimens have focused on eliminating the infected cells rather than treating the virus directly. Methods for doing this have included surgery, cryotherapy or caustic agents applied to warts, and topical application of cytotoxins such as podo-phyllin (502,503).These approaches have low success rates because of a high recurrence rate of the warts. Whereas the bulk of the wart can be removed by this method, the infected basal cells that provide the reservoir for continued viral genome replication are difficult to remove. One approach to overcoming this barrier comes from the observation that the warts may clear without treatment, presumably because of an immune response (504). This assertion is bolstered by observations that HPV-associated warts in HIV-positive patients responded to antiretroviral treatment (505, 506). Attempts to bolster the immune response led to treatment with interferon-a by injection into the infected tissue, but analogous to the response to interferon-a as an HBV treatment, interferon induction of an immune response has seen only limited success (507-509).

Induction of an interferon-mediated response by small molecule inducers of interferon has shown more success. Imiquimod (1-(2-methylpropyl)-lH-imidazo(4,5-c)quinolin-

4-amine) (62) and the related compound

5-28463 (63) induce an interferon-a-mediated response (510,511). They have shown efficacy as immunomodulators against lesions caused by both herpesviruses and papillomaviruses (512,513).In a placebo-controlled trial, 40%of patients experienced complete clearance of warts when treated with a 5% imiquimod cream for 8 weeks; no patients receiving placebo showed complete clearance (514). Three-quarters of the treated patients had a 50% reduction in wart area versus 8% with placebo. Of the patients who cleared the warts, 80% remained free of warts during a 10-week follow-up period. Greater than 50% of the patients reported mild-to-moderate localized side affects as a result of treatment, with no systemic effects reported. Similar results were noted in a 16-week study with 5% imiquimod, but 1% miquimod was ineffective (14%versus 52% complete clearance) (515). Note that the improved results with imiquimod versus direct injection of interferon could be a result of an indirect effect of imiquimod on interferon induction. This effect is mediated by cyto-kines, which may also result in regulation of other factors that promote regression of the lesions. These trials demonstrated that a local interferon response is beneficial in a subset of papillomavirus-infected patients, but that it is not universally applicable. Factors that identify patients for whom this treatment is beneficial have yet to be identified.

A combination of vidaribine (8) and podo-phyllin (a DNA polymerase inhibitor and a were tested in a 6-week topical application to 28 patients with cervical intraepithelial neoplasia (516). This treatment resulted in regression of the lesions and loss of detectable HPV DNA in 80% of the patients. However, 30%of patients for whom treatment resulted in regression of lesions relapsed during a 13-month follow-up period, indicating that longer treatments or additional combinations of drugs were needed for effective elimination of the proliferating cells.

5-fluorouracil(5-FU) (83)has been used as a topical application for treatment of warts

with mixed results. In two small studies, the majority of patients cleared the warts, with a low recurrence rate (517,518). However, in a placebo-controlled trial of 40 subjects with weekly application of a cream containing the treatment for 4 weeks, fewer of the 5-FU treated patients showed regression of HPV at 4-6 months post-treatment than the placebo-treated patients, indicating that the 5-FU may have actually exacerbated the disease (519).

Photodynamic therapy mediated by 5-ami-nolevulinic acid (ALA) has been tested as a treatment for papillomavirus-induced low-grade cervical intraepithelial neoplasia (520). The basis of this approach is that the ALA accumulates in the proliferating tissue and sensitizes those cells to visible light. At 9 months post-treatment, 95% of the patients showed improvement in PAP smears, and 80% had no detectable virus. Side effects were minimal and transient.

Cidofovir (5) has shown efficacy in selectively blocking proliferation of HPV-infected cells. This is an attractive application of cido-fovir because in treating papillomavirus infection it can be applied topically, which limits its negative side effect profile (521, 522). However, the mechanism for this inhibition is not immediately obvious because HPV does not encode a polymerase. Selectivity for HPV-in-fected cells implies a mechanism whereby the cellular polymerase of infected cells is more affected by cidofovir than that of uninfected cells. One mechanism has been identified by Johnson and Gangemi (523). In cell culture studies designed to determine the metabolic fate of cidofovir, the authors noted that in infected cells, cidofovir was readily converted to its fully phosphorylated form. However, in un-infected cells, most of the cidofovir was in the form of a choline adduct. Cidofovir inhibited proliferation of infected cells with an EC,, =

200 nM, whereas 1000 nM inhibited normal cell growth by about 15%. This loss of proliferative capacity was maintained when drug was removed after a 1-week treatment. In uninfected cells, greater than 75% of the cidofo-vir was in the form of a choline adduct. In infected cells, greater than 75% of the cidofo-vir was phosphorylated. Thus, the concentration cf cidofovir converted to polymerase substrate was considerably higher in infected cells. This factor, plus the ability to treat warts topically, may limit the toxic effects of cidofovir sufficiently to make it a practical treatment.

Using a rabbit model of papillomavirus infection, a 1%cidofovir cream applied for 18 days delayed the appearance of warts and decreased their size when applied within 1 week of infection (524). Its effectiveness decreased as the delay after infection increased. On the other hand, a related study where treatment was twice daily for 8 weeks found complete regression of the warts when treatment was delayed until 4 weeks after infection (525). Ad-efovir (76) also gave moderate activity. In about 50% of the warts treated with cidofovir, recurrences were noted with longer monitoring times. When this treatment was combined with vaccination with DNA coding for papillomavirus proteins El, E6, and E7, the recurrence rate dropped from 53 to 15% (526). Vaccination alone was not an effective treatment in this study.

Treatment of 15 women with stage III cervical intraepithelial neoplasia with 1%cidofo-vir three times every other day resulted in removal of histological signs of the lesion in 7 of 15 patients. Four of those patients had undetectable levels of papillomavirus DNA. Two patients did not respond, and the remainder showed limited responses (527).

Respiratory papillomatosis is a rare but often debilitating and difficult to treat disease. A case has been reported where cidofovir alone was insufficient at reversing the growth of lesions in an advanced case (528). However a combination of treatment with cidofovir (5 mg/kg every 2 weeks) and interferon a-2b led to a significant reduction in pulmonary lesions and complete regression of endobronchial lesions after 12 months of treatment.

The above studies concentrated on elimination of infected cells; few attempts to take on the virus directly have been reported. One such approach has been to identify compounds that cause release of zinc from the zinc binding sites if E6 (529, 530). Loss of zinc is associated with loss of capacity of E6 to bind to cellular proteins with which it interacts. In this case, the goal is not to block viral propagation but to interfere with the progression of the infected cell to malignancy. An initial screen identified compounds that were able to eject zinc from E6 and block binding of E6 to two of its cellular cofactors. One of these compounds, 4, 4'-dithiodimorpholine (84) was

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