Human Papillomavirus (HPV) is a common group of viruses responsible for epithelial infections. While many HPV types are cleared naturally, a subset is classified as high-risk due to their ability to cause cancer. HPV type 45 (HPV45) is a highly oncogenic type and a significant public health concern worldwide. It is consistently ranked among the most carcinogenic HPV types, following only HPV16 and HPV18 in its global contribution to cancer cases.
The Molecular Structure and Classification of HPV45
HPV45 is a non-enveloped virus whose genetic material is contained within a protein shell, or capsid. The viral genome consists of a circular, double-stranded DNA molecule approximately 8,000 base pairs in length. This genome contains open reading frames (ORFs) categorized into Early (E) and Late (L) genes.
The Early genes (E1 through E7) are involved in viral replication, transcription, and host cell transformation. E1 and E2 regulate the replication and maintenance of the viral DNA within the host cell’s nucleus. The Late genes (L1 and L2) encode the structural proteins that assemble to form the outer viral capsid. HPV45 is phylogenetically classified into the alpha-7 species, grouping it with other high-risk types like HPV18. The viral proteins E6 and E7 are designated as the primary oncogenes.
Transmission and Viral Pathogenesis
Transmission of HPV45 occurs primarily through intimate skin-to-skin contact, typically during sexual activity. The virus targets the basal epithelial cells of mucosal surfaces, such as the cervix and anogenital region. Infection requires access to these deeper cell layers, usually following micro-abrasions in the epithelial lining.
Once inside the basal layer, the viral DNA establishes itself as a circular, non-integrated unit called an episome, maintaining a low copy number. The viral life cycle is tied to the host cell’s differentiation program. The virus only expresses its full complement of genes and produces new infectious particles as the keratinocytes migrate outward and mature. In the upper, differentiated cell layers, high levels of viral replication and capsid protein production occur, allowing for the release of new virions as the cells shed.
Mechanisms of Oncogenesis
The progression from persistent infection to cancer is driven by the sustained expression of the HPV45 E6 and E7 oncoproteins. These two proteins dismantle the host cell’s natural safeguards against uncontrolled growth, known as tumor suppressor pathways. The E6 oncoprotein targets the cellular tumor suppressor protein p53 for destruction.
E6 recruits the host cell enzyme E6AP ubiquitin ligase to tag p53 with ubiquitin molecules, marking it for rapid degradation by the proteasome machinery. The loss of p53 eliminates a key cellular checkpoint responsible for stopping the cell cycle or initiating cell death in response to DNA damage. This allows damaged cells to survive and multiply.
E7 and Cell Cycle Deregulation
Simultaneously, the E7 oncoprotein targets the retinoblastoma protein (pRb). E7 binds to pRb, functionally inactivating it and disrupting its complex with the E2F transcription factor. The inactivation of pRb releases E2F, which activates the transcription of genes necessary for the cell to transition from the G1 resting phase into the S phase of DNA synthesis.
This forces the infected epithelial cell into an uncontrolled growth state, which is necessary for the virus to complete its replication cycle. The combined inactivation of both p53 and pRb by E6 and E7 bypasses fundamental tumor suppression mechanisms, leading directly to malignant transformation. HPV45 is associated with a range of cancers, most notably cervical cancer, where it accounts for approximately 5% of cases worldwide. It has a particular propensity for causing cervical adenocarcinoma, a more aggressive form of cervical cancer that originates in the glandular cells. Furthermore, HPV45 is one of the high-risk types found in a smaller percentage of anogenital and head and neck squamous cell carcinomas.
Host Immune Response and Preventive Measures
The host immune system attempts to clear HPV infection, primarily relying on cellular immunity, specifically cytotoxic T-lymphocytes (CTLs). The virus employs several strategies to evade immune detection, contributing to its ability to establish persistent infection. Since the virus infects the basal layer and does not cause cell lysis or inflammation upon entry, it avoids triggering an immediate, robust immune response.
The E-proteins, including E6 and E7, actively suppress the host’s innate immune signaling pathways, such as downregulating the production of type I interferons. This allows the virus to maintain a low profile in the basal epithelial compartment for extended periods. When infection persists, cellular immunity may be unable to effectively destroy the infected cells before E6 and E7 drive malignant transformation.
Prevention Strategies
Prophylactic vaccination represents the most effective preventive measure against HPV45 infection. The 9-valent HPV vaccine, the most current formulation, provides protection against nine high-risk and low-risk HPV types, including HPV45. This vaccine uses virus-like particles (VLPs) formed from the L1 capsid protein to generate a strong, neutralizing antibody response that prevents the virus from infecting the host cell.
Alongside vaccination, routine screening is a secondary prevention tool. Screening, through Pap tests and HPV DNA testing, allows for the early detection of persistent HPV infection and precancerous lesions before they progress to invasive cancer.