Viruses have evolved clever ways to sneak into our cells. They latch onto specific receptors, hitch a ride through the cell membrane, and then shed their outer layers. It's like a molecular heist, with viruses using our own cellular machinery against us.

Once inside, viruses unpack their genetic cargo, ready to hijack our cells. This process varies between enveloped and non-enveloped viruses, influencing how they spread and survive. Understanding these entry tricks is key to stopping viral invasions.

Viral Entry Mechanisms

Attachment and Receptor Interactions

• Viral attachment involves specific interactions between viral surface proteins (ligands) and host cell receptors, initiating the entry process
• Viruses exploit existing cellular uptake pathways (clathrin-mediated endocytosis, caveolin-dependent endocytosis)
• Some viruses induce macropinocytosis where cell membrane ruffles and engulfs large volumes of extracellular fluid containing viral particles
• Choice of entry mechanism depends on virus structure, host cell type, and environmental factors
• Examples of viral ligands include:
  • Hemagglutinin in influenza viruses
  • Spike protein in coronaviruses
• Host cell receptors examples:
  • ACE2 for SARS-CoV-2
  • CD4 for HIV

Endocytosis and Membrane Fusion

• Endocytosis internalizes virus within a vesicle, often triggered by receptor binding
• Membrane fusion utilized by enveloped viruses merges viral envelope with host cell membrane
• Direct penetration used by some viruses injects genetic material through cell membrane without full internalization
• Endocytosis pathways include:
  • Clathrin-mediated endocytosis (influenza virus)
  • Caveolin-dependent endocytosis (SV40 virus)
• Membrane fusion examples:
  • HIV uses gp41 protein for fusion at the cell surface
  • Influenza virus fuses within endosomes after pH-induced conformational changes

Uncoating and Genetic Material Release

Uncoating Process and Mechanisms

• Uncoating releases viral genome from protective capsid into host cell cytoplasm or nucleus
• Enveloped viruses begin uncoating with fusion of viral envelope with cellular membranes, exposing nucleocapsid
• Non-enveloped viruses undergo conformational changes from cellular triggers, leading to capsid destabilization and genome release
• Endosomal acidification triggers conformational changes in viral proteins, crucial for many uncoating processes
• Some viruses use host cell proteases to degrade capsid proteins, facilitating genome release
• Uncoating may occur in stages:
  • Partial disassembly at cell surface or in endosomes
  • Complete genome release in cytoplasm or nucleus

Timing and Cellular Factors

• Timing and location of uncoating critical for successful viral replication
• Uncoating process influences host's ability to detect and respond to infection
• Cellular factors involved in uncoating:
  • pH changes in endosomes (influenza virus)
  • Cellular chaperones (adenovirus)
  • Proteasome activity (reovirus)
• Examples of uncoating locations:
  • Poliovirus uncoats in the cytoplasm
  • Herpesvirus uncoats at the nuclear pore

Enveloped vs Non-enveloped Entry

Structural Differences and Entry Strategies

• Enveloped viruses possess lipid bilayer from host cell membranes, non-enveloped viruses lack outer membrane
• Enveloped viruses enter through membrane fusion at cell surface or within endosomes, using viral fusion proteins
• Non-enveloped viruses enter through endocytosis followed by membrane penetration or pore formation in endosomal membrane
• Enveloped viruses exploit cellular membrane fusion machinery
• Non-enveloped viruses rely on capsid protein conformational changes for entry
• Examples of enveloped viruses:
  • Influenza virus
  • HIV
  • Coronavirus
• Examples of non-enveloped viruses:
  • Adenovirus
  • Poliovirus
  • Rotavirus

Uncoating and Environmental Stability

• Enveloped virus uncoating begins with envelope fusion
• Non-enveloped viruses require more extensive capsid disassembly for uncoating
• Enveloped viruses more susceptible to environmental factors and disinfectants due to lipid envelope
• Non-enveloped viruses tend to be more stable in various environments
• Both types can use receptor-mediated endocytosis, but subsequent steps in cell entry and uncoating differ significantly
• Environmental stability examples:
  • Influenza virus (enveloped) survives on surfaces for hours
  • Norovirus (non-enveloped) can persist for weeks on surfaces

Host Cell Receptors and Tropism

Receptor Function and Viral Tropism

• Host cell receptors are specific molecules on cell surface that viruses recognize and bind to, initiating entry process
• Distribution and abundance of specific receptors on different cell types determine viral tropism, influencing infectable tissues
• Receptor binding often triggers conformational changes in viral proteins, facilitating subsequent entry steps
• Some viruses use multiple receptors or co-receptors, affecting ability to infect different cell types or species
• Affinity and specificity of virus-receptor interactions influence efficiency of viral entry and overall infection course
• Examples of receptor-mediated tropism:
  • HIV targets CD4+ T cells using CD4 and chemokine receptors
  • Hepatitis B virus targets liver cells using sodium taurocholate cotransporting polypeptide (NTCP)

Evolutionary Aspects and Therapeutic Implications

• Evolutionary changes in viral surface proteins can alter receptor usage, potentially changing host range or tissue tropism
• Understanding virus-receptor interactions crucial for developing antiviral strategies (entry inhibitors, receptor decoys)
• Receptor binding sites often conserved, making them potential targets for broad-spectrum antivirals
• Examples of receptor-based antiviral strategies:
  • Maraviroc blocks HIV entry by targeting CCR5 co-receptor
  • Neutralizing antibodies against viral attachment proteins (influenza hemagglutinin)