🦠Virology Unit 8 – Human Viral Pathogens – DNA Viruses

Introduction to DNA Viruses

• DNA viruses contain a genome composed of double-stranded DNA (dsDNA) or single-stranded DNA (ssDNA)
• Possess a protein capsid that encases and protects the viral genome
• May have an additional lipid envelope derived from the host cell membrane
• Replicate within the nucleus of the host cell, utilizing host cell machinery for transcription and replication
• Cause a wide range of diseases in humans, including respiratory illnesses, skin infections, and various cancers
• Examples of DNA viruses include Herpesviruses (Epstein-Barr virus), Adenoviruses, and Papillomaviruses (Human Papillomavirus)

Viral Structure and Genome

• DNA viruses have a genome made of DNA, which can be linear or circular, and single-stranded or double-stranded
  • Linear genomes have free ends, while circular genomes form a continuous loop
  • Double-stranded DNA is more stable and less prone to mutations compared to single-stranded DNA
• Genome size varies among DNA viruses, ranging from a few kilobases (kb) to hundreds of kilobases
• Viral capsid is composed of multiple copies of one or more types of capsid proteins, which self-assemble to form a protective shell around the genome
  • Capsid proteins are encoded by the viral genome and synthesized during replication
• Some DNA viruses (Herpesviruses) have an additional lipid envelope surrounding the capsid, which is derived from the host cell membrane during the budding process
• Structural proteins, such as tegument proteins in Herpesviruses, may be present between the capsid and the envelope, providing additional functions in the viral life cycle

Replication Cycle

• Attachment: Viral surface proteins (capsid or envelope proteins) bind to specific receptors on the host cell surface
• Entry: Viruses enter the cell through endocytosis or fusion with the cell membrane, releasing the capsid into the cytoplasm
• Uncoating: The viral capsid is disassembled, exposing the viral genome
• Replication: The viral genome is transported to the nucleus, where it is transcribed and replicated using host cell machinery
  • Early genes are expressed first, encoding proteins required for viral genome replication and regulation of host cell functions
  • Late genes are expressed after genome replication, encoding structural proteins for new virion assembly
• Assembly: Newly synthesized viral proteins and genomes are assembled into progeny virions within the nucleus
• Maturation: Virions undergo further modifications, such as the acquisition of tegument proteins and envelopes (in Herpesviruses)
• Release: Mature virions are released from the host cell through lysis or budding, ready to infect new cells

Major DNA Virus Families

• Herpesviridae: Large, enveloped dsDNA viruses that establish latent infections (Herpes Simplex Virus, Varicella-Zoster Virus, Cytomegalovirus)
• Adenoviridae: Non-enveloped dsDNA viruses that cause respiratory, gastrointestinal, and eye infections (Adenovirus)
• Papillomaviridae: Small, non-enveloped dsDNA viruses that infect epithelial cells and are associated with various cancers (Human Papillomavirus)
• Polyomaviridae: Small, non-enveloped dsDNA viruses that can cause tumors and multisystem diseases (JC virus, BK virus)
• Poxviridae: Large, complex dsDNA viruses that replicate in the cytoplasm (Smallpox virus, Molluscum Contagiosum virus)
• Parvoviridae: Small, non-enveloped ssDNA viruses that depend on helper viruses or cellular factors for replication (Parvovirus B19)

Pathogenesis and Disease

• DNA viruses employ various strategies to enter, replicate, and spread within the host, leading to disease
• Viral entry and replication can directly damage host cells through lysis or apoptosis
• Viral proteins can interfere with host cell functions, such as cell cycle regulation, leading to uncontrolled cell growth and cancer (Papillomaviruses, Polyomaviruses)
• Immune-mediated pathology: Host immune response to viral infection can cause inflammation and tissue damage
  • Cytokine storm: Overproduction of pro-inflammatory cytokines can lead to systemic inflammation and organ dysfunction
• Latency: Some DNA viruses (Herpesviruses) can establish latent infections, persisting in the host for long periods without causing symptoms
  • Reactivation of latent viruses can lead to recurrent disease (cold sores, shingles)
• Oncogenesis: Certain DNA viruses (Papillomaviruses, Epstein-Barr virus) can transform infected cells, leading to the development of cancers

Immune Response and Evasion

• Innate immune response: Early, non-specific defense against viral infection
  • Type I interferons (IFN-α/β) are produced by infected cells, inducing an antiviral state in neighboring cells
  • Natural killer (NK) cells recognize and kill virus-infected cells
• Adaptive immune response: Specific, long-lasting immunity mediated by T and B lymphocytes
  • CD8+ cytotoxic T cells recognize and eliminate virus-infected cells
  • CD4+ helper T cells support cytotoxic T cell and B cell responses
  • B cells produce virus-specific antibodies that neutralize viruses and mark infected cells for destruction
• DNA viruses have evolved various mechanisms to evade host immune responses
  • Inhibition of antigen presentation: Viral proteins can interfere with MHC class I expression, preventing recognition by cytotoxic T cells (Herpesviruses)
  • Mimicry of host immune regulators: Viruses can produce proteins that resemble host immunomodulatory molecules, suppressing immune responses (Poxviruses)
  • Interference with apoptosis: Viral proteins can block apoptosis of infected cells, allowing continued viral replication (Adenoviruses)

Diagnosis and Detection

• Clinical presentation: Diagnosis based on characteristic signs and symptoms of viral infection
• Serological tests: Detection of virus-specific antibodies (IgM, IgG) in patient serum
  • Enzyme-linked immunosorbent assay (ELISA): Quantitative measurement of antibody levels
  • Immunofluorescence assay (IFA): Visualization of antibody binding to virus-infected cells
• Viral antigen detection: Identification of viral proteins in clinical samples using antibodies
  • Direct fluorescent antibody (DFA) test: Fluorescently labeled antibodies bind to viral antigens in infected cells
• Molecular methods: Detection of viral nucleic acids in clinical samples
  • Polymerase chain reaction (PCR): Amplification and detection of viral DNA sequences
  • Real-time PCR: Quantitative measurement of viral load
• Viral culture: Isolation and growth of the virus in cell culture systems, followed by identification using immunological or molecular methods

Treatment and Prevention

• Antiviral drugs: Medications that inhibit viral replication or block viral entry into host cells
  • Acyclovir and valacyclovir: Nucleoside analogs that inhibit Herpesvirus DNA polymerase
  • Cidofovir: Nucleotide analog that inhibits viral DNA polymerase in Adenoviruses and Poxviruses
• Immunoglobulins: Passive immunization using preformed antibodies to neutralize viruses or modulate immune responses
• Vaccines: Active immunization to prevent viral infections
  • Live attenuated vaccines: Weakened viral strains that induce immunity without causing disease (Varicella vaccine)
  • Inactivated vaccines: Killed viruses that stimulate an immune response (Hepatitis A vaccine)
  • Subunit vaccines: Purified viral proteins that elicit protective immunity (Hepatitis B vaccine)
  • Virus-like particle (VLP) vaccines: Self-assembling viral capsid proteins that mimic the structure of the virus (Human Papillomavirus vaccine)
• Infection control measures: Practices to prevent the spread of viral infections
  • Hand hygiene, personal protective equipment (gloves, masks), and proper disinfection of surfaces
  • Isolation of infected individuals to minimize transmission