Biology of Human Papillomavirus Infection and Immune Therapy for HPV-Related Head and Neck Cancers

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Incidence of human papillomavirus infection

Key Abbreviations: Biology of HPV Infection

ACIPAdvisory Committee on Immunization Practices
CDCCenters for Disease Control
CINCervical intraepithelial neoplasia
CTLCytotoxic T lymphocyte
IFNInterferon
ILInterleukin
IRFInterferon Regulatory Factor
mAbMonoclonal antibody
MHCMajor histocompatibility complex
VLPViral like proteins
RRPRecurrent respiratory papillomatosis

Human papillomavirus (HPV) infection is common in the general population, and the incidence varies by age and gender. The overall prevalence

Biology of HPV infection

HPVs are small, nonenveloped DNA viruses with a double-stranded genome that encodes 6 early proteins (E1, E2, E3, E4, E5, E6, and E7) and 2 late proteins (L1 and L2), which are named based on their temporal expression pattern in the viral life cycle (Fig. 1).

Cellular progression to dysplasia and cancer

Many HPV infections are either cleared by the immune system or result in latent infections of the basal cell layer, with low viral copy numbers maintained indefinitely, or until injury or immunosuppression induces active infection. Integration of viral DNA into the host genome is a strong predictor of risk of progression from viral infection to neoplastic disease.11 Late genes (L1 and L2) and some early genes (E1 and E2) are commonly deleted with viral integration and, with the disruption of E2

Immune system and HPV

Several lines of evidence highlight the importance of a functioning immune system in controlling HPV infection and its associated neoplasms:

  • 1.

    Foremost is the observation that most immune-competent individuals infected with HPV are able to clear the infection without any clinical manifestation, and it is only 10% of infected individuals who develop HPV-related lesions.2

  • 2.

    Histologic examination of spontaneously regressing HPV-related lesions shows infiltration of CD4+ and CD8+ T cells, whereas these

Viral mechanisms to evade the immune system

HPV has evolved multiple mechanisms to evade host immunologic responses,32, 33 thereby leading to successful establishment of HPV-related lesions.

Prevention of HPV infection through vaccination

Because the immune system is so important in controlling HPV infections and the lesions associated with these viruses, in the past decade vaccination programs against HPV have been initiated in the United States and other parts of the world.

Immunotherapy for the treatment of established HPV-associated disease

The vaccination strategies discussed have focused on preventing viral infection of epithelial cells through the generation of antibody responses that recognize the viral capsid proteins. However, this strategy is not effective for treating existing infections or established HPV-related diseases. Treatment of established disease requires activation of the cellular immune system, both CD4+ and CD8+ T cells, which can recognize and eliminate virus-infected cells. The differences between

Other molecular targets for the treatment of HPV-associated disease

Although the E6 and E7 oncoproteins are the most common immunotherapeutic targets in HPV-associated cancers, the virus alters other cellular pathways that can be targeted by nonimmunologic methods.

EGFR is highly expressed in a large percentage of head and neck cancers57 and a monoclonal antibody against the receptor (cetuximab) has been found to have clinical efficacy in head and neck cancer.58 The HPV-16 viral protein E5, in particular, has effects on EGFR trafficking in the cell and enhances

Challenges and future directions of immunotherapy for HPV-associated cancers

Although targeted immunotherapeutic strategies have great promise in the treatment of HPV-associated disease, significant challenges remain. The role of regulatory T cells in contributing to a local immunosuppressive microenvironment and in suppressing cytotoxic T-cell function in cancers is increasingly being appreciated.73 The function of these regulatory T cells is to modulate activated T-cell function to prevent autoimmunity. However, in the setting of cancer immunotherapy, the regulatory T

Summary

HPV is a ubiquitous virus that causes a wide range of human diseases, including a growing subset of oropharyngeal carcinomas. Significant progress has been made within the past decade in designing and implementing preventative vaccination programs against HPV. However, there are a variety of societal and economic challenges in implementing these vaccination programs, and the burden of HPV and its related cancers will continue until these challenges are addressed. Therefore, therapeutic vaccines

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References (77)

  • A. Hong et al.

    Relationships between epidermal growth factor receptor expression and human papillomavirus status as markers of prognosis in oropharyngeal cancer

    Eur J Cancer

    (2010)
  • J. Walker et al.

    Expression of human papillomavirus type 16 E7 is sufficient to significantly increase expression of angiogenic factors but is not sufficient to induce endothelial cell migration

    Virology

    (2011)
  • J.S. Saldivar et al.

    COX-2 overexpression as a biomarker of early cervical carcinogenesis: a pilot study

    Gynecol Oncol

    (2007)
  • E.F. Dunne et al.

    Prevalence of HPV infection among females in the United States

    JAMA

    (2007)
  • P.E. Castle et al.

    A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica

    J Infect Dis

    (2005)
  • N. Munoz et al.

    Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results

    J Infect Dis

    (2004)
  • M.L. Gillison et al.

    Prevalence of oral HPV Infection in the United States, 2009-2010

    JAMA

    (2012)
  • G. D'Souza et al.

    Oral sexual behaviors associated with prevalent oral human papillomavirus infection

    J Infect Dis

    (2009)
  • G. D'Souza et al.

    Six-month natural history of oral versus cervical human papillomavirus infection

    Int J Cancer

    (2007)
  • C.B. Buck et al.

    Arrangement of L2 within the papillomavirus capsid

    J Virol

    (2008)
  • C.B. Buck et al.

    Maturation of papillomavirus capsids

    J Virol

    (2005)
  • R.C. Kines et al.

    The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding

    Proc Natl Acad Sci U S A

    (2009)
  • P. Peitsaro et al.

    Integrated human papillomavirus type 16 is frequently found in cervical cancer precursors as demonstrated by a novel quantitative real-time PCR technique

    J Clin Microbiol

    (2002)
  • P.A. Lazo

    The molecular genetics of cervical carcinoma

    Br J Cancer

    (1999)
  • M. Pett et al.

    Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis?

    J Pathol

    (2007)
  • C.C. Ragin et al.

    The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus

    J Dent Res

    (2007)
  • P.M. Howley

    Role of the human papillomaviruses in human cancer

    Cancer Res

    (1991)
  • I. Bourgault Villada et al.

    Spontaneous regression of grade 3 vulvar intraepithelial neoplasia associated with human papillomavirus-16-specific CD4(+) and CD8(+) T-cell responses

    Cancer Res

    (2004)
  • A.B. Moscicki et al.

    Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type

    J Infect Dis

    (2004)
  • W.F. Cheng et al.

    Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen

    J Clin Invest

    (2001)
  • J.J. Carter et al.

    Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection

    J Infect Dis

    (2000)
  • J.J. Carter et al.

    Human papillomavirus 16 and 18 L1 serology compared across anogenital cancer sites

    Cancer Res

    (2001)
  • I. Jochmus-Kudielka et al.

    Antibodies against the human papillomavirus type 16 early proteins in human sera: correlation of anti-E7 reactivity with cervical cancer

    J Natl Cancer Inst

    (1989)
  • K.S. Anderson et al.

    Serum antibodies to the HPV16 proteome as biomarkers for head and neck cancer

    Br J Cancer

    (2011)
  • M. Matloubian et al.

    CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection

    J Virol

    (1994)
  • M.J. Welters et al.

    Frequent display of human papillomavirus type 16 E6-specific memory T-helper cells in the healthy population as witness of previous viral encounter

    Cancer Res

    (2003)
  • A. de Jong et al.

    Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6

    Cancer Res

    (2004)
  • M. Nakagawa et al.

    Cytotoxic T lymphocyte responses to E6 and E7 proteins of human papillomavirus type 16: relationship to cervical intraepithelial neoplasia

    J Infect Dis

    (1997)
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      These therapies, however, have been shown to increase toxicity and side effects, which can have a detrimental impact on the lives of women with this cancer [12,13]. While most HPV infections can be eradicated by the immune system, only a small percentage of women's immune systems fail to clear the infected HPV, causing malignancy of the uterus cervix [14]. A variety of beneficial health maintenance microbes are hosted by the human body where most of these microbes are found in the gut.

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      The higher HPV prevalence in young people may be due to the intergenerational change in sexual behaviors, as well as the reduced frequency of sexual activity with advanced age. It is known that a large proportion of HPV infections are cleared by the immune system of the host, with the rate of such clearances being reported as 66% and 90% in the first and second years, respectively in repeated examinations of infected people [16]. The clearance and persistence of the infection are determined by the number of sexual partners, sexual habits, and smoking, along with the immune system of the relevant person [17].

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      In HPV-associated cancers, the HPV E6 and E7 oncoproteins represent optimal specific antigens. They are constitutively expressed and presented by cancer cells and they are highly immunogenic [8]. Indeed, preclinical studies have reported that anti-HPV E7 vaccines elicited E7-specific CD8+ T cells in tumor-bearing mouse models.

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