Principles of Medical Virology¶
Chapter 195 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Viral (incl. HIV) · Chapter 195
Key Clinical Points¶
- Viruses are obligate intracellular parasites requiring host cell machinery (ribosomes, enzymes) to replicate and produce progeny.
- Structural differences exist between enveloped viruses (susceptible to soap/alcohol) and unenveloped viruses (resistant to detergents).
- Viral replication pathways vary significantly based on the nature of the genome (e.g., (+) RNA vs. (-) RNA vs. dsDNA).
- Retroviruses utilize reverse transcriptase to convert (+) ssRNA into dsDNA, which integrates into the host genome as a provirus.
- Host innate immunity recognizes viral molecules via pattern recognition receptors (TLRs, RIG-I, MDA5, cGAS) to induce interferon (IFN).
- Viral evolution occurs through antigenic drift (sequence variation) and antigenic shift (genome reassortment in segmented viruses like influenza).
- Cytopathic effect (CPE) refers to cell damage/death resulting from the takeover of host cellular metabolism by viral processes.
- Post-acute infection syndromes (PAIS), such as long COVID, result from persistent replication, autoimmunity, or tissue damage.
- Diagnostic methods include nucleic acid amplification (PCR/RT-PCR), antigen detection (EIA, immunofluorescence), and hemagglutination assays.
- Viral classification is based on genome type, capsid symmetry, envelope presence, and host cell tropism.
DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): Viruses are obligate intracellular parasites that must enter cells to replicate and propagate themselves to spread to other cells. • Etymology: Derived from the Latin word for "poison" or "toxin" due to host cell injury. • Basic Structure: Simplest life forms; minimum requirements include a nucleic acid genome and a protein coat (capsid). • Replication Mechanism: Do not divide by division; instead, they disassemble inside cells → use host machinery (ribosomes, enzymes) for synthesis → assemble progeny → release as extracellular virions. • Cytopathic Effect (CPE): Damage to the cell resulting from the inhibition of normal metabolic pathways during viral takeover.
1.1 Virus Structure¶
• Virion: The minimal particle consisting of a nucleic acid genome and a protein capsid.
1.2 Envelope and Capsid Symmetry¶
• Capsid Composition: Made of repeating protein subunits (capsomers) due to limited coding capacity. • Symmetry Types: ◦ Icosahedral or spherical symmetry (based on icosahedron with 20 triangular faces). ◦ Helical symmetry. ◦ Complex structures (e.g., poxviruses). • Envelope: A lipid envelope may surround the capsid; presence of an envelope affects environmental stability and susceptibility to detergents.
EPIDEMIOLOGY¶
• Systemic Spread: Can occur via lymph or bloodstream (viremia) → can lead to disseminated infection. • Tissue-Specific Spread: ◦ Skin: Leads to classic rashes (e.g., measles). ◦ Nervous System: Transsynaptic spread along neuronal pathways (e.g., Rabies virus from periphery to CNS).
2.1 Molecular Epidemiology¶
• Genotypic Tracking: Uses direct sequencing, polymorphism analysis of restriction sites, and PCR. • Clinical Utility: Identifies specific strains (e.g., SARS-CoV-2 variants) and determines if a virus has been transmitted between individuals.
2.2 Transmission Routes¶
• Entry Points: ◦ Mucosal surfaces (oral, respiratory, nasal). ◦ Body openings (inhalation or ingestion). ◦ Skin breaks (e.g., insect bites for Zika/Dengue; skin breaches for Papillomaviruses and HSV).
ETIOLOGY & PATHOPHYSIOLOGY¶
• General Replication Cycle: Binding → Entry → Uncoating → Transport to site of replication → Transcription (mRNA) → Translation (proteins) → Genome replication → Assembly → Egress. • Entry Mechanisms: ◦ Binding: To specific receptors or charged molecules on the cell surface. ◦ Pathways: ◦ Fusion of envelope with plasma membrane. ◦ Endocytosis (clathrin-mediated, macropinocytosis, micropinocytosis, or caveolar) → followed by fusion with endosome membrane. ◦ Lysis of endosome or formation of pores in the endosome.
3.2 Viral Replication Strategies¶
• Positive-Strand RNA Viruses: ◦ Examples: Picornaviruses, caliciviruses, hepeviruses, togaviruses, flaviviruses, coronaviruses. ◦ Mechanism: Translated directly in cytoplasm → polyprotein produced → cleaved by proteases into nonstructural (replication) and structural proteins. ◦ Replication Site: Often in membrane sacs to protect from host response. ◦ Release: Budding or cell lysis. • Negative-Strand RNA Viruses: ◦ Examples: Rhabdoviruses, filoviruses, paramyxoviruses, influenza, peribunyaviruses, arenaviruses. ◦ Requirement: Must use virion-associated transcriptase to create mRNA first. ◦ Segmented Genomes: Influenza (8 segments), Peribunyaviridae (3 segments), Hantaviridae (3 segments), Nairoviridae (3 segments), Arenaviridae (2 segments). ◦ Location: Peribunyaviruses/Arenaviruses replicate in cytoplasm; Influenza replicates in the nucleus. • Double-Stranded RNA Viruses: ◦ Examples: Reovirus, rotavirus. ◦ Mechanism: Transcribed by virion-associated transcriptase → replication in cytoplasmic "factories" → release via cell lysis. • Double-Stranded DNA Viruses: ◦ General Rule: Transported to nucleus for transcription/replication. ◦ Evading Silencing: ◦ Papillomaviruses/Papovaviruses: Coated with nucleosomal chromatin in virion → not recognized as foreign. ◦ Adenoviruses: Coated with a viral protein to hide genome from host detection. ◦ Herpesviruses: Not coated in virion → rapidly loaded with histones by host → use viral enhancer/protein to drive transcription. • Single-Stranded DNA Viruses: ◦ Example: Parvoviruses. ◦ Mechanism: Delivered to nucleus → converted to dsDNA by host enzymes → transcribed by RNA polymerase II. • Retroviruses: ◦ Genome: Two identical positive-strand ssRNA molecules. ◦ Process: Reverse transcriptase converts RNA to dsDNA → Integrase integrates DNA into host chromosome → forms a provirus.
CLINICAL FEATURES¶
• Stages of Infection: 1. Entry → 2. Primary replication/disease at entry site → 3. Spread through host → 4. Secondary replication/disease at new sites → 5. Persistence or clearance → 6. Transmission.
4.1 Long-Term Effects of Infection¶
• Post-Acute Infection Syndromes (PAIS): Includes long COVID, post-dengue fatigue, and post-polio syndrome. ◦ Potential Causes: ◦ Persisting viral replication or antigens. ◦ Activation of autoimmune responses. ◦ Alteration of endogenous bacteria/viruses. ◦ Irreparable tissue damage.
DIFFERENTIAL DIAGNOSIS¶
• Classification Criteria: Based on genome type (RNA/DNA, ss/ds), capsid symmetry (helical, icosahedral, complex), envelope presence, replication mode, and tropism. ◦ Note: Table 195-1 summarizes these major families.
5.1 Distinguishing Virus Families¶
• Picornaviridae: (e.g., Polio, Rhinovirus) → (+) RNA, No Envelope, Icosahedral. ◦ Caliciviridae: (e.g., Norovirus) → (+) RNA, No Envelope, Icosahedral. ◦ Hepeviridae: (e.g., Hepatitis E) → (+) RNA, No Envelope, Icosahedral. ◦ Matonaviridae: (e.g., Rubella) → (+) RNA, Yes Envelope, Icosahedral. ◦ Togaviridae: (e.g., Dengue, Zika, West Nile) → (+) RNA, Yes Envelope, Icosahedral/Helical. ◦ Coronaviridae: (e.g., SARS-CoV-2) → (+) RNA, Yes Envelope, Helical. ◦ Rhabdoviridae: (e.g., Rabies) → (–) RNA, Yes Envelope, Helical. ◦ Filoviridae: (e.g., Ebola, Marburg) → (–) RNA, Yes Envelope, Helical. ◦ Pneumoviridae: (e.g., RSV) → (–) RNA, Yes Envelope, Helical. ◦ Paramyxoviridae: (e.g., Measles, Mumps) → (–) RNA, Yes Envelope, Helical. ◦ Orthomyxoviridae: (e.g., Influenza A, B, C) → (–) RNA, 8 segments, Yes Envelope, Helical. ◦ Peribunyaviridae/Hantaviridae/Nairoviridae: (–) RNA, 3 segments, Yes Envelope, Helical. ◦ Arenaviridae: (e.g., Lassa fever) → (–) RNA, 2 segments, Yes Envelope, Helical. ◦ Sedoreoviridae/Spinareoviridae: (e.g., Rotavirus, Reovirus) → dsRNA, No Envelope, Icosahedral. ◦ Retroviridae: (e.g., HIV, HTLV) → (+) RNA, 2 segments, Yes Envelope, Icosahedral. ◦ Hepadnaviridae: (e.g., Hepatitis B) → dsDNA with ss portions, Yes Envelope, Icosahedral. ◦ Parvoviridae: (e.g., Parvovirus B19) → ssDNA, No Envelope, Icosahedral. ◦ Papillomaviridae/Polyomaviridae/Adenoviridae: dsDNA, No Envelope, Icosahedral. ◦ Orthoherpesviridae: (e.g., HSV, VZV, EBV) → dsDNA, Yes Envelope, Icosahedral. ◦ Poxviridae: (e.g., Smallpox) → dsDNA, Yes Envelope, Complex.
DIAGNOSTIC APPROACH¶
- Biologic Assays: Used to measure infectivity by assessing the ability of a sample to infect animals or cell cultures.
- Nucleic Acid Detection (PCR/RT-PCR): → Direct PCR for DNA detection. → RT-PCR for RNA detection (requires reverse transcription step). → Multiplex PCR for detecting multiple pathogens simultaneously.
- Antigen Detection: → Immunofluorescence (IF): Uses fluorophore-conjugated antibodies to visualize antigens in tissue/cells. → Enzyme Immunoassays (EIA): Uses enzyme-linked antibodies and colorimetric substrates; used in rapid test kits.
- Hemagglutination: Measures the ability of viruses to cross-link and agglutinate red blood cells.
- Quantification: → Electron Microscopy (EM) for virion particle count. → PCR/RT-PCR for viral genome copy number. → Titer calculation based on the inverse of the last dilution causing hemagglutination.
MANAGEMENT & TREATMENT¶
- Supportive Care: Primary management for acute infections to manage symptoms and host stability.
- Antiviral Therapy: Target specific stages of the viral life cycle: → Entry inhibition. → Replication suppression. → Assembly interference.
- Monitoring: Long-term monitoring required for chronic or latent infections (e.g., HIV, HSV).
- Special Considerations: Adjust treatment based on host factors (age, comorbidities) and potential for antiviral drug resistance.
COMPLICATIONS & PROGNOSIS¶
• Prognosis Factors: Determined by virus type, host immune status, and speed of intervention. • Complications: ◦ Immunosuppression. ◦ Organ failure. ◦ Oncogenic transformation (cancer). ◦ Long-term sequelae (PAIS).
SPECIAL POPULATIONS¶
• Host Factors: Age, comorbidities, and genetic predispositions significantly influence disease severity and treatment outcomes.
KEY PEARLS & HIGH-YIELD POINTS¶
• Enveloped vs. Unenveloped: Enveloped viruses (e.g., Measles, Coronaviruses) are inactivated by soap/alcohol; Unenveloped (e.g., Norovirus) require stronger disinfectants like hypochlorite. • Clinical Trap: Do not confuse viral persistence with reactivation of a latent infection. • Clinical Trap: Do not misinterpret PAIS as a new acute infection.
Reference Tables¶
TABLE 195-1 Major Families of Human Pathogenic Viruses FAMILY Picornaviridae¶
Harrison's 22e, p.1480
| FAMILY | REPRESENTATIVE VIRUSES | TYPE OF RNA/DNA | LIPID ENVELOPE |
|---|---|---|---|
| Picornaviridae | Coxsackievirus Echovirus Enteroviruses, including poliovirus Rhinoviruses Hepatitis A virus |
(+) RNA | No |
| Norovirus | (+) RNA | ||
| Hepeviridae | Hepatitis E virus | (+) RNA | No |
| Rubella virus | (+) RNA | ||
| Togaviridae | Eastern equine encephalitis virus Western equine encephalitis virus |
(+) RNA | Yes |
| Yellow fever virus Dengue virus St. Louis encephalitis virus West Nile virus Zika virus Hepatitis C virus Hepatitis G virus |
(+) RNA | ||
| Coronaviridae | SARS-CoV-1 SARS-CoV-2 Middle East respiratory syndrome virus |
(+) RNA | Yes |
| Rabies virus Vesicular stomatitis virus |
(–) RNA | ||
| Filoviridae | Marburg virus Ebola virus |
(–) RNA | Yes |
| Respiratory syncytial virus | (–) RNA | ||
| Paramyxoviridae | Parainfluenza virus Newcastle disease virus Mumps virus Rubeola (measles) virus |
(–) RNA | Yes |
| Influenza A, B, and C viruses | (–) RNA, 8 segments | ||
| Peribunyaviridae | California encephalitis virus | (–) RNA, 3 segments | Yes |
| Hantavirus | (–) RNA, 3 segments | ||
| Nairoviridae | Crimean–Congo hemorrhagic fever virus | (–) RNA, 3 segments | Yes |
| Lymphocytic choriomeningitis virus Lassa fever virus South American hemorrhagic fever virus |
(–) RNA, 2 segments | ||
| Sedoreoviridae | Rotavirus | dsRNA, 11 segments | No |
| Reovirus Colorado tick fever virus |
dsRNA, 10–12 segments | ||
| Retroviridae | Human T lymphotropic virus 1 and 2 Human immunodeficiency virus 1 and 2 |
(+) RNA, 2 identical segments | Yes |
| Hepatitis B virus | dsDNA with ss portions | ||
| Parvoviridae | Parvovirus B19 | ssDNA | No |
| Human papillomaviruses | dsDNA | ||
| Polyomaviridae | JC virus BK virus Merkel cell polyoma virus |
… | … |
| Human adenoviruses | dsDNA | ||
| Orthoherpesviridae | Herpes simplex virus 1 and 2 Varicella-zoster virus Epstein-Barr virus Cytomegalovirus Human herpesvirus 6 Human herpesvirus 7 Kaposi’s sarcoma–associated herpesvirus |
dsDNA | Yes |
| Variola (smallpox) virus Orf virus Molluscum contagiosum virus |
dsDNA |