Viral Entry Mechanisms: Attachment and Receptor Binding
📌 Viruses are obligate intracellular parasites and are generally too large to diffuse across the plasma membrane, requiring host transport pathways for entry.
📌 For most viruses infecting eukaryotes and prokaryotes, attachment is determined by the binding of viral particles to specific host cell receptors; this initial interaction is often random collision followed by specific binding.
📌 Receptors are generally not required for viruses infecting fungi (which often remain inside the cell) or plant viruses, which enter via mechanical damage (e.g., insect feeding).
📌 Since 1985, technological advances (like recombinant DNA and flow cytometry) have accelerated the identification of receptors, moving beyond the initial knowledge of sialic acid as the influenza receptor.

Cellular Receptors and Binding Diversity
📌 Viral receptors can be protein molecules (like CD4 or the Poliovirus Receptor, CD155), glycolipids (SV40), or carbohydrates (sialic acid for influenza).
📌 These cellular proteins generally serve normal cellular functions and are co-opted by viruses for entry; for example, SARS-CoV-2 uses the ACE2 receptor.
📌 Viruses can utilize one or multiple receptors for attachment and internalization (e.g., HIV-1 requires two receptors, CD4 and a chemokine receptor).
📌 Different viruses can share the same receptor (e.g., Adenovirus and Coxsackievirus B3 share the CAR receptor), or viruses within the same family (like Rhinoviruses) can bind distinct receptors.

Mechanisms of Viral Entry and Intracellular Transport
📌 Because the cytoplasm is crowded, materials like virus particles do not simply diffuse to the nucleus; entry relies on motor-driven transport along microtubules.
📌 Viruses enter via fusion at the plasma membrane (common for some enveloped viruses like Herpesvirus) or via various forms of endocytosis (macropinocytosis, receptor-mediated endocytosis).
📌 Fusion at the plasma membrane is tightly regulated, often requiring a conformational change triggered by the initial receptor binding, exposing a hydrophobic fusion protein (e.g., HIV-1 utilizing one or two receptors).
📌 Viruses entering via endocytosis (e.g., Influenza, SARS-CoV-2) rely on the acidification of the endosome (low pH) to trigger conformational changes in glycoproteins, exposing fusion peptides that mediate membrane fusion (often involving a hairpin intermediate).

Viral Egress of Genetic Material
📌 Non-enveloped viruses like Adenovirus release DNA after endocytosis; low pH triggers the release of membrane-solubilizing peptides that poke holes in the endosome, allowing the particle to travel to the nuclear pore where capsid disassembly occurs.
📌 For Poliovirus and other picornaviruses, receptor binding alone can catalyze a pore formation (umbilicus) at one of the 12 five-fold axes of symmetry, releasing RNA directly into the cytoplasm.
📌 Reoviruses utilize a unique strategy: they survive initial lysis in the lysosome because the outer shell is degraded, leaving a hydrophobic inner particle that can then poke through the lysosomal membrane.

Key Points & Insights
➡️ Fusion of viral and host membranes is a highly regulated process to prevent non-specific fusion, controlled by factors such as pH change, receptor engagement, protease cleavage, or the presence of specific endosomal fusion receptors (like NPC1 for Ebola).
➡️ The choice of receptor type and cleavage mechanism dictates the entry route; for example, SARS-CoV-2 uses TMPRSS2 for surface fusion in lung cells, explaining why endosomal inhibitors like hydroxychloroquine were ineffective clinically.
➡️ A single amino acid polymorphism (e.g., 529Y in CDHR3) in the Rhinovirus C receptor can lead to tenfold higher receptor levels, directly correlating with increased severity of wheezing and asthma in children exposed to the virus.
➡️ DNA viruses too large for the nuclear pore (like Adenovirus and Herpesvirus) utilize motor transport to reach the pore, where the capsid is disassembled or opened, allowing the genome to enter.

📸 Video summarized with SummaryTube.com on Nov 27, 2025, 01:31 UTC