8.1 Herpesviruses and their subfamilies

Herpesviruses are a diverse family of DNA viruses that cause a range of human diseases. They're split into three subfamilies: Alpha, Beta, and Gamma, each with unique characteristics and infection patterns.

These viruses are masters of persistence, establishing lifelong latent infections in specific cell types. They can reactivate under certain conditions, causing recurrent symptoms and posing challenges for treatment and prevention.

Herpesvirus subfamilies and diseases

Classification and characteristics

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• Herpesviridae family divides into three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae
• Classification stems from biological properties including host range, replication cycle duration, cytopathology, and latency characteristics
• Herpesviruses exhibit varying degrees of host specificity
  • Some infect a narrow range of hosts (HSV-1 primarily infects humans)
  • Others have a broader host range (EBV can infect various primate species)

Alphaherpesvirinae

• Includes Herpes Simplex Virus 1 and 2 (HSV-1, HSV-2) and Varicella-Zoster Virus (VZV)
• Associated diseases:
  • HSV-1: oral herpes (cold sores)
  • HSV-2: genital herpes
  • VZV: chickenpox (primary infection) and shingles (reactivation)
• Characterized by rapid replication cycle and establishment of latency in sensory ganglia

Betaherpesvirinae

• Comprises Cytomegalovirus (CMV) and Human Herpesvirus 6 and 7 (HHV-6, HHV-7)
• Associated diseases:
  • CMV: congenital CMV infection, mononucleosis-like syndrome in adults
  • HHV-6: roseola infantum (sixth disease)
  • HHV-7: roseola infantum, febrile illnesses in children
• Features slower replication cycle and establishment of latency in secretory glands, lymphoreticular cells, and kidneys

Gammaherpesvirinae

• Includes Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV)
• Associated diseases:
  • EBV: infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma
  • KSHV: Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease
• Characterized by tropism for lymphoid cells and establishment of latency in lymphoid tissues

Structure and replication of herpesviruses

Viral structure

• Enveloped, double-stranded DNA viruses with distinctive icosahedral capsid
• Tegument layer surrounds capsid, containing viral proteins important for initial stages of infection
• Viral genome ranges from 120-230 kbp, encoding 70-200 genes
  • Variations exist among different herpesvirus species (HSV-1: ~152 kbp, EBV: ~172 kbp)
• Envelope contains viral glycoproteins crucial for attachment and entry into host cells

Replication cycle

• Attachment: viral glycoproteins bind to specific host cell receptors
  • HSV-1 glycoprotein D binds to nectin-1 or HVEM receptors
• Entry: fusion of viral envelope with cell membrane or endocytosis
• Uncoating: nucleocapsid transported to nuclear pore, viral DNA released into nucleus
• Gene expression follows coordinated cascade:
  • Immediate-early genes: transcriptional regulators
  • Early genes: enzymes for DNA replication
  • Late genes: structural proteins
• DNA replication occurs in nucleus using rolling circle mechanism
  • Produces concatemeric DNA cleaved and packaged into capsids
• Assembly and egress:
  • Nucleocapsids acquire tegument proteins
  • Envelopment occurs by budding through nuclear membrane and cellular organelles

Latency and reactivation in herpesviruses

Latency mechanisms

• Viral genome exists as circular episome in nucleus of specific cell types
• Minimal gene expression during latency
• Latency-associated transcripts (LATs) crucial for:
  • Maintaining latent state
  • Protecting infected cells from apoptosis
• Epigenetic modifications regulate latent viral genomes:
  • Histone modifications (acetylation, methylation)
  • DNA methylation

Latency characteristics

• Different herpesvirus subfamilies establish latency in distinct cell types:
  • Alphaherpesvirinae: neurons (HSV in trigeminal ganglia)
  • Betaherpesvirinae: lymphocytes and monocytes (CMV in CD34+ hematopoietic progenitor cells)
  • Gammaherpesvirinae: B lymphocytes (EBV in memory B cells)
• Latency programs vary among viruses:
  • HSV: nearly complete transcriptional silencing
  • EBV: multiple latency programs with varying gene expression profiles

Reactivation

• Triggered by various stimuli:
  • Stress (physical or emotional)
  • Immunosuppression (HIV infection, organ transplantation)
  • Hormonal changes (menstruation, pregnancy)
• Molecular switch from latency to lytic replication involves:
  • Expression of immediate-early genes
  • Activation of transcriptional activators (HSV ICP0, EBV ZEBRA)
• Reactivation leads to resumption of lytic replication cycle
• Clinical manifestations may differ from primary infection (VZV reactivation causing shingles)

Epidemiology and transmission of herpesviruses

Global distribution and prevalence

• Herpesviruses ubiquitous pathogens with worldwide distribution
• Seroprevalence rates vary among geographic regions and socioeconomic groups
  • Higher rates often observed in developing countries and lower socioeconomic populations
  • HSV-1 seroprevalence: ~67% globally, higher in Africa (~87%)
  • CMV seroprevalence: ~83% in developing countries, ~54% in developed countries

Transmission routes

• Close contact with infected bodily fluids primary mode of transmission
  • Saliva (HSV-1, EBV)
  • Genital secretions (HSV-2)
  • Blood (CMV, KSHV)
• Vertical transmission from mother to child occurs for some herpesviruses
  • CMV leading cause of congenital infections (~0.6% of live births in developed countries)
• Age of primary infection varies among different herpesviruses:
  • Childhood: HHV-6 (peak incidence at 6-12 months)
  • Adolescence/adulthood: EBV, HSV-2

Risk factors and special populations

• Coinfection with multiple herpesviruses common
  • Can lead to more severe clinical manifestations
  • May alter immune responses to individual viruses
• Immunocompromised individuals at higher risk for severe infections and reactivations:
  • HIV/AIDS patients (increased risk of CMV retinitis, KSHV-associated malignancies)
  • Transplant recipients (CMV reactivation leading to graft rejection)
• Occupational exposure risks for healthcare workers and childcare providers
  • Increased risk of acquiring CMV infection