Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk

Abstract

Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.

Keywords: RNA interference; cancer; human immunodeficiency virus (HIV); human papillomavirus (HPV); nanoparticles; primary immunodefciencies; squamous cell carcinoma; transplant.

Figure 1

HPV pathogenesis and treatment in at-risk individuals. (A) HPV pathogenesis, persistent infection, and progression to cancer. Primary infection occurs when HPV gains access to basal cells through microlesions or damage to the skin. Upon viral replication, HPV can evade the immune response resulting in persistent disease. E6 and E7 oncogenes disrupt the cell cycle, which can result in persistent disease, cellular transformation and HPV-driven carcinoma. (B) Describes the three main immunodeficiencies 1) Primary immunodeficiencies relating to inborn errors of immunity, 2) Secondary immunodeficiencies relating to those under immunosuppressive drugs 3) Acquired immunodeficiencies relating to people living with HIV/AIDS. The major HPV pathologies caused by high-risk HPV and low-risk HPV strains are identified on the extreme right-hand side panel (HPV-driven disease) (C) Identifies the main treatments currently available and the next-generation therapeutics currently under investigation. Created with BioRender.com.

Figure 2

Incidence of HPV associated malignancies in 2020. (A) Age standardised rate per 100,000 for men with cancer of the anus, oropharyngeal, larynx, penis, lips, and oral cavity. (B) Age standardised rate per 100,000 for females with cancer of the anus, cervix uteri, larynx, oropharynx, lip, and oral cavity. International Agency for Research on Cancer, World Health Organisation 2020.

Figure 3

RNAi pathways. Post Transcriptional Gene Silencing (PTGS) inducing short interfering ribonucleic acid (siRNA) operate via the actions of the ribonucleic acid (RNA) induced silencing complex (RISC), a multiprotein nuclease complex comprised of Argonaute-2 (Ago-2), Dicer, TAR RNA binding protein, protein kinase interferon-inducible double stranded RNA dependent activator, and GW domain protein 182 in humans. The antisense strand binds Ago-2 and is incorporated into the RISC complex. The antisense strand guides the complex to the targeted mRNA product, where Ago-2 facilitates the cleavage of, and subsequent degradation of the messenger ribonucleic acid (mRNA). Transcriptional Gene Silencing (TGS) inducing siRNA operate via the actions of the RNA induced transcriptional silencing (RITS) complex, a multiprotein complex comprised of Argonaute-1 (Ago-1) and other, yet unidentified, proteins in humans. The antisense strand binds Ago-1 and is incorporated into the RITS complex, where it guides the complex into the cell nucleus and targets the gene promoter. Heritable epigenetic modifications result in compaction of chromatin structures surrounding the target site, preventing the transcription of gene products, and silencing expression. Created with BioRender.com.

Figure 4

Comparative diagram of in vivo / ex vivo gene deliveries. In-vivo gene delivery via the use of nanoparticles. Conjugation of the nanoparticle designed for the target cell and the siRNA designed against the targeted genetic material are applied to the patient based of disease characteristics (i.e topical application for HPV infected cervical cells). Ex-vivo gene delivery via the use of lentiviral vectors requiring the collection of patient cells, transduction with the constructed lentiviral vector before re-introduction of the transduced patient cells back into the patient. Created with BioRender.com.