Papillomaviruses Lecture Notes

World Health Organization - HPV Overview

I. Introduction

• Title: One in three men worldwide infected with genital human papillomavirus (HPV)

• Date: 1 September 2023

• Source: Departmental news

II. General Information on Papillomaviruses

• Family: Papillomaviridae

• Species: 133 recognized species across 53 genera (as of 2024)

• Host Specificity: Strict host and tissue specificity

• Infection Targets: Stratified squamous epithelial cells

• Chronic Infections: Establishes in basal stem cells

• Health Impact: Causes common/gential warts, various cancers (high-risk strains)

III. Structure and Replication

A. Virion Structure

• Type: dsDNA, Baltimore Group 1

• Shape: Icosahedral (T=7), non-enveloped

• Size: 60 nm diameter

• Capsid Proteins: Major L1 (360 copies), Minor L2 (76 copies)

B. Genome Structure

• Type: Circular dsDNA (~8kb)

• Packaging: Complexed with cellular histones

• Proteins: 7 non-structural (E1–E7), 2 structural (L1, L2)

IV. HPV Proteins and Functions

• E1: Origin binding helicase

• E2: DNA binding, transcription regulation

• E4: Facilitates viral transmission

• E5: Promotes cell growth & immune evasion

• E6 & E7: Immune evasion and cell cycle progression

• L1 & L2: Capsid assembly and genome packaging

V. Replication Cycle

A. Phases

1. Viral entry, uncoating, DNA amplification

2. Differentiation-triggered amplification in non-dividing cells

B. Processes

• Entry: Micro-abrasion binding via L1 and host HSPGs

• Uncoating: Triggered by endocytosis, promotes nuclear translocation

• Gene Expression: Occurs in the nucleus using host RNA polymerase

C. Genome Replication

• The genome replication in HPV is tightly linked to the differentiation of the host epithelial cells. After viral entry, the E1 and E2 proteins are crucial for initiating replication. E1 binds at the origin of replication, unwinding the DNA and allowing the host machinery to synthesize new viral DNA.

• Strand Displacement Mechanism: The replication involves a strand-displacement mechanism where the leading strand is synthesized continuously while the lagging strand is synthesized in Okazaki fragments. The E1 helicase unwinds the DNA, and the DNA polymerase synthesizes the new strands while the viral genome is maintained in the basal layers of the epithelium during low-activity phases.

• Regulation: Replication is regulated by the E2 protein, which not only binds to the viral DNA but also interacts with the host cell's transcription factors, ensuring that the viral life cycle is synchronized with the differentiation state of the host cell. In differentiated cells, this triggers an increase in the genome copy number, which is essential for viral propagation.

D. Assembly and Maturation

• Capsid Formation: Following genome replication, HPV utilizes the host cell's machinery for virion assembly. L1 and L2 proteins bind the replicated genomes in the nucleus to form the capsid. The L1 protein is particularly abundant and forms the majority of the capsid structure, while L2 plays a supporting role in associating with the genome and facilitating proper packaging.

• Transport to Cell Surface: After assembly, the completed capsids are transported to the inner surface of the host cell. The process may involve interactions with cytoskeletal elements to move the virions to the plasma membrane.

• Release: Mature virions are released from the host cell primarily through lytic pathways, where the host cell undergoes programmed cell death or lysis, allowing for the spread of new infectious particles to adjacent cells, perpetuating the cycle of infection.

VI. Immune Evasion and Cancer Association

• Detection Avoidance: Weak inflammatory response - no lysis or viraemia

• E6 inactivates tumour suppressor p53

• HPV down regulates innate immune senses in keratinocytes

• Cancers: ~5% of human cancers (especially cervical) linked to HR-HPV

VII. Prevention and Screening

• Methods: Routine Pap smear screening

• HPV Vaccine: Protects against high-risk strains

VIII. Treatment and Research

• Treatments: Excision, cryotherapy, LEEP

• Research: Ongoing trials for therapeutic vaccines

IX. Conclusion

• HPV's immune evasion strategies contribute to persistence and oncogenic potential. Continued research needed for effective treatments and vaccines against HPV-related diseases.