8.2 Papillomaviruses and polyomaviruses

Papillomaviruses and polyomaviruses are small, non-enveloped DNA viruses that can cause various diseases in humans. These viruses share similarities in structure and replication, but differ in genome size, capsid composition, and gene organization.

Both virus families have oncogenic potential, with high-risk HPVs linked to cervical and other cancers. Prevention and treatment strategies focus on vaccination, screening, and managing infections, especially in immunocompromised individuals.

Papillomavirus vs Polyomavirus Structure

Genome and Capsid Characteristics

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• Papillomaviruses and polyomaviruses consist of small, non-enveloped DNA viruses belonging to Papillomaviridae and Polyomaviridae families
• Both viruses contain circular, double-stranded DNA genomes
  • Papillomaviruses possess larger genomes measuring approximately 8 kb
  • Polyomaviruses have smaller genomes measuring approximately 5 kb
• Capsid structure differs between the two virus types
  • Papillomaviruses have an icosahedral capsid composed of 72 capsomeres
  • Polyomaviruses feature a smaller icosahedral capsid with 72 pentameric capsomeres

Gene Organization and Protein Expression

• Both viruses encode early (E) and late (L) proteins
• Papillomaviruses exhibit more complex gene organization compared to polyomaviruses
  • Papillomaviruses encode six early proteins (E1, E2, E4, E5, E6, E7) and two late proteins (L1, L2)
  • Polyomaviruses typically encode three early proteins (large T antigen, small t antigen, middle T antigen) and three late proteins (VP1, VP2, VP3)
• Protein functions vary between the two virus types
  • Papillomaviruses utilize E1 and E2 proteins for viral genome replication
  • Polyomaviruses employ large T antigen (LT) for genome replication

Replication Cycle Differences

• Both viruses share similar overall replication steps including nuclear entry, genome amplification, and progeny virion assembly
• Papillomaviruses require epithelial differentiation for complete replication
  • Early gene expression occurs in basal epithelial cells
  • Genome amplification and late gene expression happen in upper epithelial layers
• Polyomaviruses can replicate in various cell types without requiring cellular differentiation
• Regulatory mechanisms differ between the two virus types
  • Papillomaviruses employ a complex regulatory mechanism involving E2 protein
  • Polyomaviruses primarily rely on large T antigen for regulation of viral gene expression

Oncogenic Potential of Papillomaviruses and Polyomaviruses

High-Risk HPV Oncogenesis

• High-risk human papillomaviruses (HPV 16, 18) associate with cervical, anogenital, and oropharyngeal cancers
• Oncogenic potential of high-risk HPVs stems primarily from E6 and E7 oncoproteins
  • E6 targets p53 tumor suppressor pathway, leading to inhibition of apoptosis
  • E7 targets pRb tumor suppressor pathway, promoting uncontrolled cell proliferation
• Persistent infection with high-risk HPV types can progress to cervical intraepithelial neoplasia (CIN)
  • CIN can further develop into cervical cancer through multi-step cellular transformation process
• Low-risk HPV types (HPV 6, 11) possess limited oncogenic potential
  • Typically cause benign warts or condylomas
  • Rarely progress to malignant lesions

Polyomavirus Oncogenic Mechanisms

• Merkel cell polyomavirus (MCPyV) associates with Merkel cell carcinoma, a rare aggressive skin cancer
• MCPyV oncogenic mechanism involves two key steps:
  • Integration of viral DNA into host genome
  • Expression of truncated large T antigen, which drives cellular transformation
• Other polyomaviruses (BK virus, JC virus) demonstrate limited oncogenic potential in immunocompetent individuals
  • May contribute to cancer development in immunosuppressed patients
  • BK virus associates with urothelial carcinomas in transplant recipients
  • JC virus potentially contributes to colorectal cancer and brain tumors in immunocompromised individuals

Papillomavirus and Polyomavirus Infections

Clinical Manifestations of HPV Infections

• HPV infections cause various clinical manifestations depending on virus type and infection site
• Cutaneous HPV infections lead to different types of warts
  • Common warts (verruca vulgaris) typically appear on hands and feet
  • Plantar warts develop on the soles of feet
  • Flat warts often occur on face and legs
• Mucosal HPV infections result in genital warts and precancerous lesions
  • Condyloma acuminata caused by low-risk HPV types (HPV 6, 11)
  • Cervical intraepithelial neoplasia (CIN) caused by high-risk HPV types (HPV 16, 18)
• HPV-related oropharyngeal cancers exhibit distinct characteristics
  • Often affect younger, non-smoking individuals
  • Generally have better prognosis compared to tobacco and alcohol-induced cancers

Polyomavirus-Associated Diseases

• BK virus causes nephropathy and hemorrhagic cystitis in immunosuppressed patients
  • Particularly affects kidney transplant recipients
  • Can lead to graft loss if left untreated
• JC virus acts as causative agent of progressive multifocal leukoencephalopathy (PML)
  • Severe demyelinating disease of central nervous system
  • Primarily affects immunocompromised individuals (HIV/AIDS patients, transplant recipients)
• Merkel cell polyomavirus infection typically remains asymptomatic in immunocompetent individuals
  • Can lead to Merkel cell carcinoma in susceptible populations (elderly, immunosuppressed)

Prevention and Treatment of Papillomavirus and Polyomavirus Diseases

HPV Prevention and Management

• Prophylactic HPV vaccines effectively prevent infection with high-risk HPV types
  • Bivalent vaccine (Cervarix) targets HPV 16 and 18
  • Quadrivalent vaccine (Gardasil) targets HPV 6, 11, 16, and 18
  • Nonavalent vaccine (Gardasil 9) targets additional high-risk types (HPV 31, 33, 45, 52, 58)
• Cervical cancer screening programs crucial for early detection and prevention
  • Pap smears detect abnormal cervical cells
  • HPV DNA testing identifies high-risk HPV infections
• Treatment of HPV-related lesions varies based on type and location
  • Surgical excision removes visible lesions (LEEP, conization)
  • Cryotherapy destroys abnormal tissue through freezing
  • Topical medications (imiquimod, podophyllin) stimulate immune response or inhibit viral replication

Polyomavirus Disease Management

• No specific antiviral treatments currently available for polyomavirus infections
• Management primarily focuses on reducing immunosuppression and providing supportive care
• BK virus-associated nephropathy treatment strategies include:
  • Reducing immunosuppression to allow immune system to control viral replication
  • Administering cidofovir or leflunomide as potential antiviral agents
  • Monitoring viral load to assess treatment efficacy
• JC virus-related PML prevention involves careful monitoring and risk stratification
  • Particularly important for patients receiving certain immunomodulatory therapies (natalizumab)
• Ongoing research aims to develop targeted therapies for polyomavirus-associated diseases
  • Potential antiviral agents targeting specific viral proteins
  • Immunotherapies for Merkel cell carcinoma (immune checkpoint inhibitors)