Human Papillomavirus (HPV) is a widespread virus that infects skin and mucous membranes. Understanding its basic biological makeup and how it interacts with human cells is important for comprehending its impact on the body at a cellular level.
The HPV Viral Structure
HPV is a small, non-enveloped virus, measuring about 50 to 60 nanometers in diameter. It has an icosahedral capsid, a regular protein shell composed of 72 pentameric capsomers. This outer shell encases the viral genome, a single, circular double-stranded DNA molecule approximately 8,000 base pairs long.
The capsid is primarily formed by two structural proteins: L1 (major capsid protein) and L2 (minor capsid protein). The L1 protein (55 kDa) makes up approximately 80% of the viral proteins and is arranged into 360 molecules to form the 72 capsomers. The L2 protein (70 kDa) is less abundant and not fully exposed on the virion’s surface. Both L1 and L2 are encoded by the virus and are essential for assembling new viral particles.
How HPV Infects Cells
HPV infection begins when the virus gains access to the basal layer of epithelial cells. This occurs through micro-abrasions or small wounds in the skin or mucosal surfaces, which expose the underlying basement membrane. The L1 major capsid protein plays a primary role in initial attachment by binding to heparan sulfate proteoglycans (HSPGs) on the basement membrane or cell surface.
Binding of L1 to HSPGs induces conformational changes in both L1 and L2 proteins. Subsequently, the L2 minor capsid protein is cleaved by furin, exposing an L1 surface that binds to a specific cell surface receptor on keratinocytes that have migrated to cover the wound. The virus then enters the cell, primarily through an endocytic pathway, often clathrin-mediated, and is transported to endosomes.
Viral Life Cycle within the Body
After entering the cell, the HPV genome, complexed with L2, escapes the endosome and travels to the cell nucleus within 24 hours, where viral gene transcription begins. The HPV life cycle is closely linked to the differentiation program of the host epithelial cells. In the basal layer, the viral DNA initially replicates as a low-copy plasmid.
As infected basal cells differentiate and move towards the upper layers of the epithelium, the virus enters a productive phase. During this phase, viral early genes (E1, E2, E4, E5, E6, E7) are expressed, regulating viral DNA replication and interacting with host cell machinery. For instance, E1 and E2 proteins work together to initiate viral DNA replication, with E2 also functioning as a transcriptional regulator. Later, in differentiated cells, the late genes (L1 and L2) are expressed, leading to the amplification of the viral genome and the assembly of new viral particles.
HPV and Cellular Changes
The activity of HPV’s early proteins, particularly E6 and E7, alters host cell growth and differentiation. These proteins maintain infected cells in an undifferentiated state, necessary for viral replication. High-risk HPV E6 and E7 proteins interfere with host cell tumor suppressor proteins, such as p53 and retinoblastoma protein (pRb).
E7 binds to pRb, disrupting its interaction with transcription factor E2F, driving S-phase gene expression and promoting cell cycle progression. Simultaneously, E6 promotes the degradation of p53, which normally induces apoptosis in cells with DNA damage or unscheduled proliferation, allowing infected cells to evade programmed cell death. This combined action of E6 and E7 can lead to uncontrolled cell proliferation and genomic instability, contributing to benign growths like warts or, with persistent high-risk HPV infection, potentially precancerous lesions and cancer.