Immunotherapy of HPV infection-caused genital warts using low dose cyclophosphamide

Abstract

Condylomata acuminata (CA), caused by human papillomavirus (HPV), is a common sexually transmitted disease with half a million new cases diagnosed in the United States per year and an annual increase in incidence in China. Conventional treatments, including topical cytotoxic agents, surgical excision and physical therapies, are traumatic, cause local side-effects and are invalid for subclinical or latent infection. Exploring immune approaches to eradicate HPV in CA therapeutics are highly desirable. Recent evidence shows that FOXP3⁺ regulatory T (Treg) cells are accumulated in genital warts where they mediate immunosuppression. Intriguingly, a low dose of cyclophosphamide (CY), a conventional chemotherapy drug, can selectively target Treg cells, thereby enhancing the function of HPV-specific T cells and NK cells leading to efficient clearance of HPV infection. These findings have important clinical significance, and could potentially lead to a therapeutic breakthrough for the treatment of CA.

Keywords::

• cyclophosphamide
• HPV infection
• immunotherapy
• regulatory T cell

Acknowledgements

We thank Yonghong Wan from McMaster University for assistance in editing this article.

Financial & competing interests disclosure

This work was partially supported by the National Natural Science Foundation of China (81102224, 30972667), the National Basic Research Program of China (2014CB542103) and the National Science Fund for Distinguished Young Scholars of China (81225021). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Condylomata acuminata caused by HPV type 6 or 11 is a common sexually transmitted disease with increased incidence in China.

• HPV infects basal keratinocytes and causes genital warts with a variable latent period.

• Spontaneous regression occurs in most HPV type 6 or 11 infection-caused lesions; however, some lesions evade anti-HPV immunity and finally develop into warts.

• Multiple treatments including surgical excision and topical physical therapies are commonly associated with high recurrence rates, especially in the presence of latent HPV in the so-called clinically normal epithelium outside the treatment area.

• Treg cells participate in the infection process of various viruses, including HPV type 6 or 11 infection.

• Treg cells inhibit multiple components of the immune system and can mediate virus immune evasion.

• Cyclophosphamide (CY) is a chemotherapeutic agent widely used in malignancies as well as autoimmune disorders.

• Low-dose CY may act as immune modulator to enhance anti-HPV immune responses by targeting Treg cells, leading to clearance of infectious viruses.

• Reduced intracellular ATP levels in Treg cells confer the sensitivity of Treg cells to low-dose CY.

Notes