Human Papillomavirus (HPV) is one of the most common sexually transmitted infections globally. While most infections are transient and harmless, persistent infection with specific high-risk HPV types, such as HPV16 and HPV18, is the primary cause of several human cancers. These high-risk strains are responsible for nearly all cases of cervical cancer, as well as a significant portion of anal, vaginal, vulvar, penile, and oropharyngeal cancers. The ability of these viruses to drive malignant transformation stems from the actions of two small viral proteins, E6 and E7. These proteins hijack the machinery of the host cell, leading to the uncontrolled growth characteristic of cancer.
Defining the High-Risk Oncoproteins
The E6 and E7 proteins are classified as viral oncogenes because they actively promote tumor formation. They are encoded by the early region of the HPV genome and are continuously expressed in infected epithelial cells that progress toward malignancy. The distinction between high-risk HPV types and low-risk types (which typically only cause benign warts) lies in the potency of their E6 and E7 proteins, which are more effective at disrupting cellular defense mechanisms.
For a persistent infection to progress into cancer, the viral DNA often integrates into the host cell’s chromosomes. This integration usually results in the loss of viral genes that regulate E6 and E7 expression. Consequently, the E6 and E7 oncogenes are expressed continuously and at high levels, driving sustained damage to the cell. This constant production makes them indispensable for the survival and proliferation of the cancer cell.
Hijacking the Cell Cycle Regulators
The core mechanism by which E6 and E7 cause cancer involves neutralizing two primary tumor suppressor proteins. E6 targets the p53 protein, often called the “guardian of the genome.” Normally, when a cell experiences damage, p53 initiates repair processes or triggers programmed cell death (apoptosis) if the damage is too severe.
The E6 protein promotes the destruction of p53 by recruiting E6-Associated Protein (E6AP), an E3 ubiquitin ligase. E6 forms a complex with E6AP and p53, tagging p53 with ubiquitin molecules (polyubiquitination). This process marks p53 for rapid degradation by the proteasome machinery, eliminating the cell’s primary defense against accumulating mutations.
The E7 protein targets the Retinoblastoma protein (pRb), which functions as a molecular brake on the cell cycle. In healthy cells, pRb binds to and inactivates the E2F family of transcription factors, preventing the cell from moving from the resting G1 phase into the DNA synthesis S phase. E7 binds directly to the active form of pRb, interacting with its pocket domain.
E7 binding inactivates pRb by preventing it from binding to E2F and also marks pRb for proteasomal degradation, similar to E6’s action on p53. The destruction of pRb releases the E2F transcription factors, which activate the genes necessary for cell division. This premature entry into the cell cycle promotes uncontrolled cell proliferation.
The Path to Malignant Transformation
The combined neutralization of p53 and pRb by E6 and E7 dismantles the cell’s regulatory system. Inactivating pRb causes the cell to lose its G1 checkpoint control and enter uncontrolled proliferation, dividing without necessary external signals. The continuous production of E6 and E7 drives the cell into a permanent state of division, a hallmark of cancer.
The loss of p53 function ensures that any resulting DNA damage or genomic stress goes uncorrected. Without p53 to initiate repair or apoptosis, damaged cells survive and continue dividing, leading to the rapid accumulation of mutations. This genomic instability fuels the transformation process, allowing the cell to acquire additional cancer-promoting traits.
E6 also activates the expression of telomerase, an enzyme that maintains the ends of chromosomes, granting the cell capacity for infinite replication. This combination of uncontrolled growth, evasion of programmed cell death, and genomic instability transforms a normal epithelial cell into a perpetually dividing, malignant cell.
Therapeutic Strategies Against E6 and E7
The continuous expression of E6 and E7 in HPV-driven cancers makes them a specific therapeutic target. Since these proteins are unique to cancer cells, targeting them should spare healthy host cells, reducing side effects. Current research focuses on strategies to eliminate the proteins or the cells that express them.
Therapeutic vaccines are a promising approach, designed to train the patient’s immune system (T-cells) to recognize E6 and E7 as foreign antigens. These vaccines aim to mount a specific immune response that seeks out and destroys the HPV-positive cancer cells, and various formulations are currently being evaluated in clinical trials.
Small molecule inhibitors are being developed to directly block the destructive actions of the viral proteins. These molecules disrupt the physical interaction between E6 and E6AP, or between E7 and pRb, thereby restoring the function of the tumor suppressor proteins. Restoring p53 and pRb activity would force the cancer cell to stop dividing or undergo apoptosis.
Advanced gene editing technologies, such as CRISPR/Cas9, represent another strategy to directly target the viral genes. By programming guide RNA to target the E6 and E7 oncogenes, researchers can induce double-strand breaks in the viral DNA. Silencing the oncogenes successfully restores p53 and pRb function, leading to growth inhibition and cell death in HPV-positive cancer cell lines.