Understanding Persistent Oral Human Papillomavirus and Human Immunodeficiency Virus co-infection and Its Role with Oropharyngeal Cancer Induction

HIV/AIDS and Oral Health Research Program
Center for Clinical Research
Division of Extramural Research


The goal of this initiative is to solicit research to better understand the mechanisms of persistent oral human papillomavirus (HPV) and human immunodeficiency virus (HIV) co-infection as well as its role in the induction and pathogenesis of HPV-associated oropharyngeal cancers (HPV-OPC).


It is well-known that HIV infection leads to an increased risk for opportunistic infection such as persistent HPV infection among People with HIV (PWH)1. Although most oral HPV infections are asymptomatic and clear spontaneously, persistent high-risk HPV infection (e.g. HPV16) in the oral mucosa is associated with HIV infection and induction of HPV-OPC by weakening the mucosal immunity2. Previous research has found that PWH have a 2 to 4-fold increased risk for HPV-OPC as compared to HIV-negative individuals3. Recent systematic reviews and meta-analyses of several large longitudinal studies strongly suggest an epidemiologic synergistic relationship between HIV and HPV4. Regardless, there are gaps in our knowledge about the underlying mechanisms of the co-infection and the biological synergistic interactions of oral HPV and HIV, and their impact on the induction and pathogenesis of HPV-OPC.

Literature suggests that persistent HPV infection alters toll-like receptors and impairs antiviral pathways such as interferon in mucosal epithelial tissues, including within the oral cavity. While antiretroviral therapy (ART) has contributed to a revolutionary improvement in HIV/AIDS control, PWH under ART present with an altered microbial profile with increased periodontal pathogenic bacteria which can damage mucosal epithelial immune homeostasis. At the cellular level, HPV and HIV co-infection and microbiome dysbiosis can further lead to dysregulation of immune cells such as macrophages, natural killer cells, dendritic cells, mucosal associated invariant T cells and Th17 lymphocytes in mucosal epithelium. These cells are essential in the innate and adaptive immune response maintaining mucosal homeostasis and protecting opportunistic infection such as mucosal candidiasis in PWH 2, 5,6. Consequently, it is critical to identify common biological pathways activated by both viruses, especially to elucidate the mechanisms and pathogenesis of the compromised mucosal and systemic immunity followed by co-infection and symbiotic interaction of oral HPV and HIV.

The risk for HPV infection evolving into malignancy depends on the viral pheno-/geno- types and status of host immune homeostasis. Impaired oral immune integrity contributes to HPV persistence and the induction of HPV-OPC malignancy. High-risk oncogenic subtypes such as HPV-16, 18, 31, 33 and 35 are capable of transforming oral epithelial cells through the function of viral oncoproteins E6 and E7. It is hypothesized that in the favorable context, the viral genome from high-risk HPV infection is integrated into the host genome and initiates HPV-OPC development. However, the exact mechanisms and pathogenesis pertaining to how the onco-genetic antigens express in epithelial cells, weaken the immune response, and lead to the development of HPV-OPC in the context of HIV are unclear 7-9.

Gaps and Opportunities

This concept builds upon two FY2022 RFAs (Understanding Oral Human Papillomavirus (HPV) Infection, Acquisition, and Persistence in People Living with HIV (R01 Clinical Trial Not Allowed) and Understanding Oral Human Papillomavirus (HPV) Infection, Acquisition, and Persistence in People Living with HIV (R21 Clinical Trial Not Allowed))and intends to further address knowledge gaps related to our understanding of the mechanisms and pathogenesis such as immunology, onco-genomics and onco-immunology related to persistent oral HPV and HIV co-infection and HPV-OPC induction. Currently, there are a number of clinical trials testing the HPV vaccines as therapeutics for HPV related cancers in PWH (e.g. HPV Vaccine Therapy in Reducing High-Grade Cervical Lesions in Patients With HIV and HPV (COVENANT)). This initiative will advance the FY22-25 NIH Strategic Plan for HIV and HIV-Related Research to better understand oral HIV-associated comorbidities, co-infection and complications, i.e. HPV infection and associated OPC. Outcomes of this research may provide valuable insights guiding the development of highly efficient prevention and therapeutic strategies for oral HPV and HIV co-infection and discovery of mechanistic targets related to HPV-OPC treatment. It also responds to the 2022-2026 NIDCR Strategic Plan to integrate oral and general health (priority #1). NIDCR will collaborate with NCI to advance this multi-disciplinary research area (priority #5) and will provide opportunities to support innovative research and international collaboration to advance oral health in PWH.

Specific Areas of Interest

Examples of research areas that fall within the scope of this initiative include, but are not limited to:

  • Studying the epidemiology and biology of oral HPV acquisition, persistence and progression in People With HIV;
  • Exploring the mechanisms of epidemiology and biology for synergistic relationships between HIV and oral HPV infection;
  • Elucidating mechanisms related to how and to what extent HIV infection affects oral HPV infection, such as oral microbiome profile, immunologic and dynamic pathogenic changes;
  • Evaluating the impact of ART on oral microbial and immune pathogenic changes associated with oral HPV acquisition and persistence in People With HIV;
  • Uncovering the mechanisms and pathogenesis of onco-genomics and onco-immunology related to how oral HPV and HIV co-infection contribute to the induction of HPV-OPC. Relevant areas include but are not limited to: biomarkers, high-risk HPV subtypes, molecular or cellular drivers or key mucosal and systemic immunologic components contribute to oral HPV and HIV co-infection and induction of HPV-OPC.


1.     Cameron JE, Hagensee M. HPV-Associated Oropharyngeal Cancer in the HIV/AIDS Patient. Cancer Treat Res. 2019;177:131-181.

2.     Britto AMA, Goes LR, Sivro A, et al. HPV Induces Changes in Innate Immune and Adhesion Molecule Markers in Cervical Mucosa With Potential Impact on HIV Infection (PDF - 1.2 MB). Front Immunol. 2020 Sep 3;11:2078.

3.     Pullos AN, Castilho RM, Squarize CH. HPV Infection of the Head and Neck Region and Its Stem Cells. J Dent Res. 2015;94(11):1532-43.

4.     Looker KJ, Rönn MM, Brock PM, et al. Evidence of synergistic relationships between HIV and Human Papillomavirus (HPV): systematic reviews and meta-analyses of longitudinal studies of HPV acquisition and clearance by HIV status, and of HIV acquisition by HPV status. J Int AIDS Soc. 2018 Jun;21(6):e25110.

5.     Sobkowiak MJ, Davanian H, Heymann R, et al. Tissue-resident MAIT cell populations in human oral mucosa exhibit an activated profile and produce IL-17. Eur J Immunol. 2019 Jan;49(1):133-143.

6.     Kistler JO, Arirachakaran P, Poovorawan Y, et al. The oral microbiome in human immunodeficiency virus (HIV)-positive individuals. J Med Microbiol. 2015;64:1094–101.

7.     Vu HL, Sikora AG, Fu S, Kao J. HPV-induced oropharyngeal cancer, immune response and response to therapy. Cancer Lett. 2010 Feb 28;288(2):149-55.

8.     Hoffmann TK, Arsov C, Schirlau K, et al. T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer. 2006 Apr 15;118(8):1984-91.

9.     Pham CT, Juhasz M, Sung CT, et al. The human papillomavirus vaccine as a treatment for human papillomavirus-related dysplastic and neoplastic conditions: A literature review. J Am Acad Dermatol. 2020 Jan;82(1):202-212.


Last Reviewed
September 2022