In-Depth Notes on Herpesviruses, Poxviruses, & Human Papilloma Virus

Introduction

This section introduces the herpesviruses, poxviruses, and human papillomavirus, detailing the skin lesions they cause as their primary clinical manifestation.

Most viruses discussed in this chapter trigger skin lesions, such as vesicles from herpes simplex viruses (HSV) 1 and 2 and varicella-zoster virus (VZV). Müllerian skin lesions include purple macular or nodular lesions from human herpesvirus 8 (HHV-8) and fleshy papules from molluscum contagiosum virus. Human papillomavirus (HPV) leads to papillomas (warts) on skin and mucous membranes. Interestingly, cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are exceptions, as they do not induce skin lesions.

The viruses discussed generally possess DNA as their genome, with herpesviruses and poxviruses containing linear double-stranded DNA, while HPV has circular double-stranded DNA. Notably, herpesviruses and HPV replicate in the nucleus, while poxviruses replicate in the cytoplasm.

Herpesviruses Overview

Herpesviruses encompass six significant human pathogens, including HSV types 1 and 2, VZV, CMV, EBV, and HHV-8.

Structural Properties

All herpesviruses share structural similarities: they have an icosahedral core enveloped in a lipoprotein envelope, a linear double-stranded DNA genome, and lack a polymerase in the virion. These viruses are large, measuring between 120 and 200 nm in diameter, and are second in size only to poxviruses. Replication occurs in the nucleus, and herpesviruses display intranuclear inclusions and acquire their envelope through budding from the nuclear membrane. The presence of tegument proteins between the nucleocapsid and envelope is crucial for viral replication.

Latency

Herpesviruses are notable for their capacity to induce lifelong latent infections—an initial acute phase followed by asymptomatic stages where the virus remains dormant. Reactivation is often triggered by factors like sunlight, stress, or immunosuppression.

Categories of Herpesviruses

Herpesviruses categorize into three groups based on the primary site of infection and latency:

  • Alpha herpesviruses: HSV-1, HSV-2, and VZV, primarily infecting epithelial cells and establishing latency in neurons.
  • Beta herpesviruses: CMV and HHV-6, infecting various tissues.
  • Gamma herpesviruses: EBV and HHV-8, latently infecting primarily lymphoid cells.

Herpes Simplex Viruses (HSV)

HSV Types

HSV is distinguished into two types: HSV-1, primarily above the waist, and HSV-2, mostly below the waist. The diseases caused by both types include:

  • HSV-1: Acute gingivostomatitis, recurrent herpes labialis (cold sores), keratoconjunctivitis, encephalitis.
  • HSV-2: Genital herpes, neonatal herpes, and aseptic meningitis.
Replicative Cycle

The replicative cycle for HSV begins with the attachment to cell receptors, followed by fusion and release of the nucleocapsid into the cytoplasm. The viral nucleocapsid then moves to the nucleus where the viral DNA incorporates and starts the transcription of early genes by host polymerase. This leads to subsequent synthesis of viral proteins necessary for genome replication and virion assembly. However, during latency, the viral genome remains in a circular form, not integrated into cellular DNA, and expression is modulated through latency-associated transcripts (LATS).

Clinical Findings
HSV-1
  • Gingivostomatitis
  • Orolabial herpes
  • Keratoconjunctivitis and encephalitis
  • Herpetic whitlow and eczema herpeticum
HSV-2
  • Genital herpes characterized by painful vesicular lesions
  • Neonatal herpes, which is severe if primary infection occurs during the third trimester
  • Aseptic meningitis usually self-limiting
Laboratory Diagnosis

Diagnoses involve PCR and viral cultures for both types while Tzanck smears can provide rapid presumptive results via multinucleated giant cells detection.

Treatment

Acyclovir is the primary treatment, effective against both HSV-1 and HSV-2 infections, though it does not eradicate latency.

Varicella-Zoster Virus (VZV)

VZV causes chickenpox (varicella) as the primary disease and shingles (zoster) as the recurrent disease. Primary infection tends to be mild in children but severe in adults, sometimes leading to complications such as pneumonia or encephalitis. Zoster causes painful vesicles along sensory nerve pathways. Diagnosis generally employs Tzanck smear, PCR, or clinical presentation. Vaccines (Varivax for chickenpox, Zostavax, and Shingrix for shingles) have significantly reduced incidence.

Cytomegalovirus (CMV)

CMV is known for cytomegalic inclusion disease, especially congenital infections, and is a prominent cause of morbidity in immunocompromised patients. It exhibits a unique replicative cycle involving immediate-early protein translation and possesses various immune evasion strategies. Diagnosis is made through PCR and shell vial culture techniques.

Epstein-Barr Virus (EBV)

EBV is primarily associated with infectious mononucleosis; it can also lead to certain cancers. Clinical diagnosis relies on serologic tests revealing heterophile antibodies. The virus primarily infects B lymphocytes and remains latent in them, requiring mobile T-cells for immune response.

Human Papillomavirus (HPV)

HPV is primarily noted for causing papillomas or warts; some types (e.g., HPV 16 and 18) are linked to cervical and other carcinomas. HPV infects squamous epithelial cells leading to the production of koilocytes in lesions and can be diagnosed via PCR. The HPV vaccine (Gardasil 9) protects against high-risk types and associated carcinomas but does not treat existing infections.