The Catastrophic HPV/HIV Dual Viral Oncogenomics in Concert with Dysregulated Alternative Splicing in Cervical Cancer

Abstract

Cervical cancer is a public health problem and has devastating effects in low-to-middle-income countries (LTMICs) such as the sub-Saharan African (SSA) countries. Infection by the human papillomavirus (HPV) is the main cause of cervical cancer. HIV positive women have higher HPV prevalence and cervical cancer incidence than their HIV negative counterparts do. Concurrent HPV/HIV infection is catastrophic, particularly to African women due to the high prevalence of HIV infections. Although various studies show a relationship between HPV, HIV and cervical cancer, there is still a gap in the knowledge concerning the precise nature of this tripartite association. Firstly, most studies show the relationship between HPV and cervical cancer at genomic and epigenetic levels, while the transcriptomic landscape of this relationship remains to be elucidated. Even though many studies have shown HPV/HIV dual viral pathogenesis, the dual molecular oncoviral effects on the development of cervical cancer remains largely uncertain. Furthermore, the effect of highly active antiretroviral therapy (HAART) on the cellular splicing machinery is unclear. Emerging evidence indicates the vital role played by host splicing events in both HPV and HIV infection in the development and progression to cervical cancer. Therefore, decoding the transcriptome landscape of this tripartite relationship holds promising therapeutic potential. This review will focus on the link between cellular splicing machinery, HPV, HIV infection and the aberrant alternative splicing events that take place in HIV/HPV-associated cervical cancer. Finally, we will investigate how these aberrant splicing events can be targeted for the development of new therapeutic strategies against HPV/HIV-associated cervical cancer.

Keywords: alternative splicing; cervical cancer; highly active antiretroviral therapy (HAART); human immunodeficiency virus (HIV); human papillomavirus (HPV); oncovirus.

Figure 1

Viral-associated cancers: infections with viruses such as Epstein–Barr virus, HPV, hepatitis B virus, hepatitis C virus, human herpes virus, human T cell leukemia virus and HIV can lead to the development of a variety of cancers.

Figure 2

(A) Age standardised rates (ASR) (per 100,000 women per year) incidence and mortality for cervical cancer in specific regions. (B) Map showing the age standardised rate (ASR) for incidence in individual countries. (C) Map showing the age standardised rate (ASR) for mortality in individual countries [24].

Figure 3

HPV-related cancers in Africa, Asia, America and Europe. Regardless of the continent, cervical cancer is the most common HPV-associated cancer in women. Amongst men, Africa is different from America, Asia and Europe as anal cancer is the most common HPV-related cancer in Africa. In Asia, head and neck cancer and anal cancer are the most common HPV-related cancers. In America and Europe, the most common HPV-related cancer is head and neck cancer.

Figure 4

Splicing of the HPV genome. The DNA genome of HPV is made up of the long control region (LCR, not shown), the early region (E) and the late region (L). The LCR regulates transcription and replication. The genes of the early region control infection and virus expression, while genes of the late region code for the virus capsule proteins. Alternative splicing in HPV infection results from two different promoters in low-risk HPV and by a single promoter in high-risk HPV. Different isoforms of the E6 protein are found in high-risk HPV.

Figure 5

Splicing of the HIV genome. In the early stage of HIV infection, tat, rev and nef regulatory proteins are transcribed from completely spliced mRNA. Additionally, following early infection, vif, vpr, vpu and env are transcribed from partially spliced mRNA. Furthermore, non-spliced mRNA is translated to form the gal and pol structural proteins.

Figure 6

DDR and apoptosis signalling involving E6 and E7. E6 targets p53 by forming a ternary complex with E6-associated protein (E6AP), inducing the degradation of p53. Additionally, the E6 protein binds the transcriptional co-activator cAMP response element binding protein (CREB) binding protein/p300 (CBP/p300), downregulating the ability of CBP/p300 to activate p53 responsive elements. Furthermore, E7 prevents cell cycle inhibition. E7 also binds and inhibits the retinoblastoma (pRB) protein family, interfering with the pRB/E2F interaction. Normally, E2F induces the transcription of S phase genes such as cyclins A and E.