2500_Virology_5 _w2025

Virus Entry Lecture

• Instructor: Dr. J.D. Dikeakos, Schulich School of Medicine & Dentistry

• Contact: jimmy.dikeakos@uwo.ca

Lecture Objectives

• Main Objective: Understand how viruses enter host cells

• Elements:

  • Overview and concepts of viral entry

  • Viral receptor attachment

  • Host cell entry mechanisms (enveloped and non-enveloped viruses)

Major Themes in Virology

• For viruses to survive, they must:

  1. Package their genome within a particle.

  2. Transfer the genome from host to host using this particle.

  3. Genome contains the information to initiate and complete the viral infectious cycle.

  4. Establish themselves in hosts, ensuring long-term viral survival.

• The GENOME is crucial for viral function, as established in the 1950s.

Overview of Viral Infectious Cycle

• Key concept: Entry involves:

  1. Recognition of host receptor (attachment).

  2. Mechanism to release genome within the cytoplasm.

Passive Diffusion

• Viruses are too large for passive transport through host cell membranes.

Stability of Virions

• Virions must possess both stability and instability:

  • Stability varies through different stages of the infectious cycle.

Receptor Interactions

• Viruses must find the "right" receptor:

  • Random electrostatic interactions do occur but do not initiate the infectious cycle.

  • The binding of a virus to its receptor triggers the infectious cycle and allows for genome release inside the host.

  • Definitions:

    • Susceptible cell: has functional receptor for the virus.

    • Permissive cell: allows virus replication.

    • Resistant cell: has no receptor.

Importance of Host Cell Receptors

• Essential for many viruses, excluding yeast and plants.

• Some viruses require a second receptor known as a co-receptor.

Variety of Host Cell Viral Receptors

• All host cell viral receptors are surface membrane proteins.

• A receptor can recognize multiple viruses, and multiple receptors can recognize a single virus.

Example: ACE2 Receptor

• Key for the entry of SARS-CoV-2:

  • Various viruses use this receptor, with implications for viral infection.

Modes of Attachment

Non-enveloped vs. Enveloped Viruses

• Attachment differs based on the outer structure of the virus.

Non-enveloped Viruses

• Example: Picornaviridae (Poliovirus)

  • Structure: icosahedral symmetry with 60 VP proteins.

  • Single stranded RNA (+RNA) ready for infection.

Genome Release Mechanisms

• Naked virions can release their genomes at the plasma membrane:

  • Poliovirus injects RNA across the membrane after capsid change, forming a channel.

Host Cell Entry Examples

Enveloped Viruses

• Example: Influenza Virus

  • Hemagglutinin is a glycoprotein responsible for binding to host cell receptors (sialic acid).

Sialic Acid Linkages

• 2-3 linkages (avian) and 2-6 linkages (human) determine specificity for influenza strains.

Potential for Cross-species Infection

• Avian influenza can bind to 2-3 sialic acid receptors in the lower respiratory tract, while human strains prefer the 2-6 linkages in upper and lower tracts.

Viral Entry Mechanisms

• Viruses enter using cellular transport mechanisms, powered by molecular motors (active transport).

Release Triggers

• Triggers for genome release depend on locations within the cell:

  • Can occur at the cell surface, early endosome, or late endosome.

pH Impact on Release Locations

• Cell surface pH: 7.0

• Early endosome pH: 6.0 - 6.5

• Late endosome pH: 5.0 - 5.5

Non-enveloped Example: Reoviruses

• Release linked to pH-induced capsid changes and hole formation in late endosomes.

Enveloped Virus Examples

• Example: Paramyxoviridae (Measles)

  • Viral proteins mediate fusion events dependent on pH.

Ebola Virus Uptake

• Utilizes Niemann–Pick C1 (NPC1) cholesterol transporter for infection in late endosomes.

Summary/Take-Home Message

• Viruses recognize proteins on host cells for attachment, leading to viral entry and genome release at varied subcellular locations.