Questions: Viral Attachment, Tropism, and Host Cell Entry

Question 1

HIV infects helper T cells but not liver cells, even though both cell types are present in an infected person. A student suggests this is because HIV 'seeks out' immune cells. What actually accounts for this specificity?

• A. HIV contains internal signal sequences that direct it to lymphoid tissue after entry into the bloodstream
• B. HIV's gp120 surface protein binds specifically to the CD4 receptor, which is expressed on helper T cells but not on hepatocytes — receptor availability on the cell surface determines which cells can be productively infected
• C. The immune system concentrates incoming viruses in lymphoid organs, where T cells happen to be abundant
• D. HIV replicates faster in T cells because they divide more rapidly, giving the virus a selective advantage there

Answer: (B)

Viral tropism is determined at the molecular level by receptor-ligand specificity. HIV's gp120 envelope protein binds the CD4 receptor (and a co-receptor, CCR5 or CXCR4). Hepatocytes do not express CD4, so HIV cannot attach to them regardless of how much virus is present. The virus has no 'sensing' mechanism — it simply binds cells that happen to display the right receptor. This molecular lock-and-key principle explains why different viruses cause disease in different tissues and species.

Question 2

Influenza virus is taken up by receptor-mediated endocytosis and fuses with the endosomal membrane rather than with the plasma membrane at the cell surface. What specifically triggers fusion inside the endosome?

• A. Lysosomal proteases cleave the viral hemagglutinin, exposing its hydrophobic fusion peptide
• B. The acidic pH of the maturing endosome triggers a conformational change in hemagglutinin that exposes the fusion peptide and drives viral and endosomal membranes together
• C. Calcium ions released from the endosomal lumen activate the viral fusion machinery
• D. Hydrolysis of the viral RNA genome releases energy that powers the membrane fusion event

Answer: (B)

Influenza exploits the endosomal acidification that normally occurs as endosomes mature. Hemagglutinin is a spring-loaded protein: at neutral pH, it holds the fusion peptide shielded. When the endosome acidifies to pH ~5, hemagglutinin undergoes an irreversible conformational change — it extends like a harpoon and embeds its fusion peptide into the endosomal membrane, pulling the two membranes together. This pH-triggered mechanism is why drugs that prevent endosomal acidification (like chloroquine) inhibit influenza infection. It also illustrates how viruses hijack normal cellular processes for entry.

Question 3

Non-enveloped viruses enter host cells by membrane fusion, the same mechanism used by enveloped viruses like HIV and measles.

• T. True
• F. False

Answer: False

Membrane fusion requires two lipid bilayers to merge — the viral envelope and the host membrane. Non-enveloped viruses lack an outer membrane altogether; they consist only of a protein capsid surrounding the genome. Without a membrane to fuse, they must use a fundamentally different strategy: disrupting the host membrane to deliver their genome. Common mechanisms include lysis of the endosomal membrane (adenoviruses escape the endosome by rupturing it) or forming pores in the membrane. Bacteriophages take the most distinct approach — injecting their genome directly through the cell wall while the capsid remains outside.

Question 4

The specificity of the match between a viral attachment protein and its cellular receptor is the primary determinant of which host species and cell types a virus can productively infect.

• T. True
• F. False

Answer: True

This receptor-tropism relationship is the central principle of viral host range and tissue specificity. HIV-CD4, influenza hemagglutinin-sialic acid, SARS-CoV-2 spike-ACE2 — in each case the identity of the receptor constrains which cells the virus can enter. A virus cannot productively infect a cell that lacks its receptor, regardless of what happens after entry. This principle also explains species barriers: a virus adapted to a bird receptor may bind poorly to the human homolog of that receptor, limiting zoonotic transmission unless mutations improve affinity.

Question 5

Why can most viruses not easily jump between host species, and what must change at the molecular level for a successful cross-species transmission event to occur?

Model answer: Viruses are adapted to bind specific receptor molecules, and the receptor for a given viral attachment protein in one species may differ enough from the same receptor in another species that the virus cannot bind efficiently. For cross-species transmission to succeed, the viral attachment protein must acquire mutations that improve its affinity for the new host's receptor variant. For example, SARS-CoV-2's spike protein binds human ACE2 effectively because mutations in its receptor-binding domain increased affinity relative to the bat coronavirus from which it descended. Without such mutations, the virus cannot attach, enter, and replicate in the new host at levels needed to establish infection.

This is why pandemic potential is assessed partly by monitoring mutations in attachment proteins (like influenza's hemagglutinin). Each mutation that improves binding to a human receptor represents a step toward a variant capable of human-to-human transmission. The receptor-binding interface is also the primary target for neutralizing antibodies and antiviral drugs, since blocking attachment before entry prevents infection altogether.