Pathogenesis of Hepatitis A Virus (HAV)

1. The Virus - Structure

• Sherris & Ryan's Medical Microbiology, p. 480-481
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease, p. 1210

2. Transmission

3. Entry and Intracellular Replication

1. Attachment: HAV binds to specific surface receptors on hepatocytes. The primary cellular receptor is TIM-1 (T-cell immunoglobulin and mucin domain 1, also called HAVcr-1), a glycoprotein. Entry occurs via receptor-mediated endocytosis (viropexis).
2. Uncoating: The viral capsid is uncoated inside the cell.
3. Translation: Since HAV RNA is positive-sense, it acts directly as mRNA. Ribosomes bind to the internal ribosomal entry site (IRES) in a cap-independent manner, translating the single open reading frame into a large polyprotein, which is then proteolytically cleaved into mature structural and non-structural proteins.
4. Replication: The non-structural protein RNA-dependent RNA polymerase (RdRp) creates a negative-sense RNA intermediate, which serves as the template for new positive-sense genomic RNA. All replication occurs exclusively in the cytoplasm within a membrane-bound replication complex.
5. Assembly and Release: New viral genomes are packaged into newly synthesized capsid proteins. Virions are exported - primarily into bile (and to a lesser extent into serum). Cell lysis also releases virions. HAV is also known to exist in a quasi-enveloped form (eHAV) wrapped in host-derived membranes during bloodstream transit, which helps it evade immune detection.

• Goldman-Cecil Medicine, p. (block 18)
• Sherris & Ryan's Medical Microbiology, p. 481

4. Spread to the Liver and Viral Shedding

5. Mechanism of Liver Injury - Immunopathogenesis

• Viral shedding and peak viremia pre-date clinical liver injury, meaning viral replication and cell death are temporally dissociated.
• Cytotoxic CD8+ T-cell response is the primary instrument of hepatocyte destruction. HAV-specific CD8+ CTLs recognize viral peptides presented on MHC class I and kill infected hepatocytes.
• CD4+ helper T cells and IFN-γ secreting CD4+ cells amplify the response.
• Notably, nonspecific (bystander) CD8+ T-cell activation against non-HAV viral antigens has been demonstrated during acute HAV infection, and this correlates with the degree of liver injury - highlighting that the immune response is broader than just HAV-specific.
• An activated innate immune response is also evident, suggesting multiple immunologic pathways contribute simultaneously.
• HAV does not establish chronic infection, and individuals who lack robust cellular immunity (e.g., immunocompromised patients) may have less liver damage but prolonged viremia.
• Harrison's Principles of Internal Medicine 22E, p. 2693-2694

6. Histopathology of the Infected Liver

• Harrison's Principles of Internal Medicine 22E, p. 2694

7. Clinical Course and Outcomes

• Incubation period: 15-45 days
• Up to 50% of adult infections are subclinical
• Symptomatic illness: fever, anorexia, nausea, right upper quadrant pain, followed by jaundice with dark urine and clay-colored stools
• Self-limiting in the vast majority; full recovery in weeks to months
• No chronic carrier state - HAV does not integrate into the genome or persist
• Relapsing cholestatic hepatitis: HAV is the most common cause (Sleisenger & Fordtran's)
• Fulminant hepatitis with extensive liver necrosis: rare but potentially fatal, more common in elderly and those with pre-existing liver disease
• Rare extrahepatic manifestations: immune complex disorders have been linked (rarely) with HAV

8. Immunity After Infection

Summary Flowchart

Ingestion of contaminated food/water
        ↓
Replication in intestinal mucosa (incubation 15-45 days)
        ↓
Viremia → Spread to liver via bloodstream
        ↓
Receptor-mediated entry into hepatocytes (TIM-1/HAVcr-1)
        ↓
Cytoplasmic replication (IRES-mediated polyprotein → RdRp)
        ↓
Viral export into bile → fecal shedding (peak: pre-jaundice)
        ↓
Host immune recognition (innate → CD4+ & CD8+ T cells)
        ↓
CD8+ CTL-mediated hepatocyte killing + bystander activation
        ↓
Liver injury (↑ ALT/AST, jaundice)
        ↓
Clearance (IgM → IgG), self-limited recovery
        ↓ (rarely)
Fulminant hepatic failure