Viral pathogenesis is the multifaceted process by which viruses cause disease in infected hosts. It involves the interaction between viral virulence factors and host defense mechanisms, determining the outcome from asymptomatic infection to severe disease or death.
Routes of Entry
Viruses enter the host through various routes. The respiratory tract is used by influenza, rhinovirus, SARS-CoV-2, and measles virus, which enter via inhalation of aerosolized droplets and undergo local replication in respiratory epithelium before systemic spread. The gastrointestinal tract is used by rotavirus, norovirus, and poliovirus, which survive gastric acidity and infect intestinal epithelial cells or M cells of Peyer’s patches. The genitourinary tract is used by HIV, herpes simplex virus (HSV), and human papillomavirus (HPV), which enter through mucosal surfaces during sexual contact. Parenteral entry occurs when hepatitis B, hepatitis C, and HIV enter through blood or needle stick injuries, bypassing mucosal barriers. The skin is used by rabies virus (bite wounds), HSV (breaks in skin), and arboviruses (arthropod vectors).
Local versus Systemic Spread
Local infections remain at the entry site, as seen with rhinovirus in the upper respiratory tract and papillomavirus in epithelial cells. Systemic infections spread through the lymphatic system and bloodstream (viremia); for example, measles and varicella-zoster virus infect lymphoid tissues first (primary viremia) then spread to target organs (secondary viremia). Neurotropic viruses such as rabies, HSV, and poliovirus spread along neural pathways via axonal transport, bypassing humoral immunity.
Tissue Tropism
Tropism is determined by the presence of specific receptors on host cells. HIV infects CD4+ T cells, and HBV targets hepatocytes via the NTCP receptor. Intracellular factors (transcription factors, RNA splicing machinery, proteases) must be compatible with viral replication requirements. Host immune responses can also limit viral spread to certain tissues.
Mechanisms of Tissue Damage
Direct cytopathic effects of viral replication include cell lysis (poliovirus), syncytia formation (RSV, HIV), apoptosis (HIV, influenza), and inclusion body formation (rabies). Immunopathology occurs when excessive or inappropriate immune responses cause tissue damage; for example, hepatitis B and C liver damage is largely T-cell mediated, and cytokine storm in severe influenza and COVID-19 drives acute respiratory distress syndrome. Oncogenesis results from viruses such as HPV (E6/E7 oncoproteins), HBV (chronic inflammation), HTLV-1 (Tax protein), and EBV (LMP1), which promote malignant transformation through disruption of cell cycle regulation.
Host Factors in Pathogenesis
Age plays a significant role: neonates and the elderly typically experience more severe disease due to immature or senescent immune systems. Immune status is critical, as immunocompromised individuals (HIV, transplant recipients) are at higher risk for severe viral infections and reactivation of latent viruses. Genetic factors such as the CCR5-delta32 mutation confer resistance to HIV, and HLA types influence progression of HIV, hepatitis, and influenza.
Viral Evasion of Host Defenses
Antigenic variation allows influenza A to undergo antigenic drift (gradual mutation) and shift (reassortment), while HIV evolves rapidly within hosts. Many viruses interfere with interferon by inhibiting interferon induction (NS1 of influenza) or interferon signaling (HBV, HCV). Immune camouflage strategies include CMV producing MHC homologs and HSV inhibiting antigen presentation via TAP, while some viruses establish latency (HSV in neurons, HIV in resting T cells).
