Questions

Viral Immune Evasion — Questions

Study questions for Viral Immune Evasion.

Mock Exam mode

Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.

4 questions: 1 MCQ, 3 written.

High-priority (past-paper) questions only

Hepatitis C virus (HCV) establishes chronic infection in 70 to 80% of exposed adults despite a vigorous innate and adaptive response. The paradox is resolved by integrated evasion at the innate, humoral, and cellular levels.

Innate immune evasion

NS3/4A cleavage of MAVS and TRIF. The NS3/4A serine protease cleaves both the viral polyprotein and two host interferon adaptors. Cutting MAVS (mitochondrial antiviral signalling protein) abolishes RIG-I/MDA5-driven IFN-β induction; cutting TRIF abolishes TLR3-driven induction. The infected hepatocyte cannot mount a type I interferon response. NS3/4A is also the target of the -previr drugs (glecaprevir, voxilaprevir). PKR inhibition. NS5A and E2 bind and inhibit protein kinase R (which phosphorylates eIF-2α to halt translation), preserving viral translation. Downstream sabotage. HCV induces SOCS1/SOCS3 and STAT1 hypomethylation, blunting JAK-STAT responses to interferon. ISG paradox. High pre-treatment intrahepatic ISG expression and plasma CXCL10 (IP-10) predict poor interferon-α response, reflecting a saturated, exhausted antiviral system; linked to the IFNL3 (IL28B) locus, where the rs12979860 CC genotype favours clearance and response. NK suppression. E2 cross-links CD81 on natural killer (NK) cells, inhibiting NK function and dendritic cell maturation.

Humoral evasion

HVR1 escape. Hypervariable region 1 of E2 is the immunodominant neutralising target and mutates within weeks under antibody pressure. Quasispecies. NS5B lacks proofreading (mutation rate ~10⁻⁴ to 10⁻⁵; about 10¹² virions per day), so escape variants pre-exist in the swarm. Glycan shielding of E1/E2 conserved epitopes and cell-to-cell spread further evade neutralising antibody.

Cellular evasion

CD4+ help failure is the hallmark of progression to chronicity: a broad, sustained CD4+ response predicts resolution, and its loss collapses CD8+ proliferative capacity. CD8+ exhaustion follows chronic antigen exposure, with PD-1, TIM-3, LAG-3 and CTLA-4 upregulation, lost cytokine production (IFN-γ, IL-2, TNF) and reduced cytotoxicity (as in chronic HBV, LCMV and cancer). CTL escape mutations in immunodominant epitopes expand in the quasispecies. Treg expansion in the liver dampens effector function. The core protein binds C1qR to directly inhibit T cells, and dendritic cell dysfunction (plasmacytoid and conventional) impairs interferon and antigen presentation.

The tolerogenic liver compounds these as a viral sanctuary. Because innate sensing, antibody and T cell arms are all disabled, sterilising immunity does not follow natural clearance (reinfection occurs in PWID, MSM and chimpanzees) and direct-acting antiviral (DAA) cure does not protect against reinfection, with direct implications for vaccine design and elimination.

A complete answer centres on clonal, cell-associated persistence.

Persistence and spread. After reverse transcription and integration, HTLV-1 makes little infectious free virus. It spreads between cells by direct contact at the virological synapse, and it persists chiefly by driving the infected T cell to divide, so the provirus is copied by the host’s own machinery and passed to both daughter cells (clonal, mitotic spread). Host replication, not the viral enzyme, therefore maintains the infection and keeps the genome stable.

Why reverse-transcriptase inhibitors do not help. Established infection is sustained by proliferation of already-infected clones, not by ongoing reverse transcription, so inhibitors of reverse transcriptase and integrase do not lower the proviral load or treat the associated diseases; their only role is post-exposure prophylaxis, before integration is established.

Natural killer cells kill cells that have lost class I, the “missing-self” signal. HCMV restores an inhibitory signal by expressing a class I homologue (UL18) and by supplying a peptide that stabilises HLA-E, both of which engage NK inhibitory receptors. The cell therefore escapes both cytotoxic T cell recognition, through loss of classical class I, and natural killer recognition, through the decoys.

Blocking degranulation, suppressing interferon and recruiting complement regulators are real viral tactics but do not answer missing-self, and upregulating activating ligands would invite NK killing, not prevent it.

A complete answer traces the route into the memory B-cell reservoir, then maps the programmes onto the tumours.

Establishing latency. After entry into a B cell (gp350/220 binding CD21), the virus runs its full growth programme (latency III) to drive the cell to proliferate. The infected cell passes through the germinal centre and settles as a resting memory B cell, which expresses essentially no viral genes (latency 0) and so is invisible to the immune system, expressing EBNA1 only when it divides (latency I). This memory B-cell pool is the lifelong reservoir; reactivation to the lytic cycle occurs when such a cell differentiates into a plasma cell.

Mapping programmes to tumours. The programme a tumour runs reflects its origin and its visibility to T cells:

Latency I (EBNA1 only): Burkitt lymphoma and gastric carcinoma.
Latency II (adds LMP1 and LMP2): nasopharyngeal carcinoma and Hodgkin lymphoma.
Latency III (the full growth programme): the lymphomas of immunosuppression, including post-transplant and HIV-associated disease, which can only persist where T-cell control has failed.

High priorityExam-styleDiscuss immune evasion by hepatitis C virus. [6]
Model answer
Hepatitis C virus (HCV) establishes chronic infection in 70 to 80% of exposed adults despite a vigorous innate and adaptive response. The paradox is resolved by integrated evasion at the innate, humoral, and cellular levels.

Innate immune evasion

NS3/4A cleavage of MAVS and TRIF. The NS3/4A serine protease cleaves both the viral polyprotein and two host interferon adaptors. Cutting MAVS (mitochondrial antiviral signalling protein) abolishes RIG-I/MDA5-driven IFN-β induction; cutting TRIF abolishes TLR3-driven induction. The infected hepatocyte cannot mount a type I interferon response. NS3/4A is also the target of the -previr drugs (glecaprevir, voxilaprevir). PKR inhibition. NS5A and E2 bind and inhibit protein kinase R (which phosphorylates eIF-2α to halt translation), preserving viral translation. Downstream sabotage. HCV induces SOCS1/SOCS3 and STAT1 hypomethylation, blunting JAK-STAT responses to interferon. ISG paradox. High pre-treatment intrahepatic ISG expression and plasma CXCL10 (IP-10) predict poor interferon-α response, reflecting a saturated, exhausted antiviral system; linked to the IFNL3 (IL28B) locus, where the rs12979860 CC genotype favours clearance and response. NK suppression. E2 cross-links CD81 on natural killer (NK) cells, inhibiting NK function and dendritic cell maturation.

Humoral evasion

HVR1 escape. Hypervariable region 1 of E2 is the immunodominant neutralising target and mutates within weeks under antibody pressure. Quasispecies. NS5B lacks proofreading (mutation rate ~10⁻⁴ to 10⁻⁵; about 10¹² virions per day), so escape variants pre-exist in the swarm. Glycan shielding of E1/E2 conserved epitopes and cell-to-cell spread further evade neutralising antibody.

Cellular evasion

CD4+ help failure is the hallmark of progression to chronicity: a broad, sustained CD4+ response predicts resolution, and its loss collapses CD8+ proliferative capacity. CD8+ exhaustion follows chronic antigen exposure, with PD-1, TIM-3, LAG-3 and CTLA-4 upregulation, lost cytokine production (IFN-γ, IL-2, TNF) and reduced cytotoxicity (as in chronic HBV, LCMV and cancer). CTL escape mutations in immunodominant epitopes expand in the quasispecies. Treg expansion in the liver dampens effector function. The core protein binds C1qR to directly inhibit T cells, and dendritic cell dysfunction (plasmacytoid and conventional) impairs interferon and antigen presentation.

The tolerogenic liver compounds these as a viral sanctuary. Because innate sensing, antibody and T cell arms are all disabled, sterilising immunity does not follow natural clearance (reinfection occurs in PWID, MSM and chimpanzees) and direct-acting antiviral (DAA) cure does not protect against reinfection, with direct implications for vaccine design and elimination.
High priorityExam-styleExplain how HTLV-1 persists and spreads within the host, and why antiretroviral reverse-transcriptase inhibitors do not treat established disease. [5]
Model answer
A complete answer centres on clonal, cell-associated persistence.

Persistence and spread. After reverse transcription and integration, HTLV-1 makes little infectious free virus. It spreads between cells by direct contact at the virological synapse, and it persists chiefly by driving the infected T cell to divide, so the provirus is copied by the host’s own machinery and passed to both daughter cells (clonal, mitotic spread). Host replication, not the viral enzyme, therefore maintains the infection and keeps the genome stable.

Why reverse-transcriptase inhibitors do not help. Established infection is sustained by proliferation of already-infected clones, not by ongoing reverse transcription, so inhibitors of reverse transcriptase and integrase do not lower the proviral load or treat the associated diseases; their only role is post-exposure prophylaxis, before integration is established.
MCQ
Human cytomegalovirus (HCMV) downregulates surface major histocompatibility complex (MHC) class I to evade cytotoxic T cells. How does it avoid the resulting natural killer (NK) cell "missing-self" attack?
- A. It blocks natural killer cell degranulation enzymes
- B. It presents a class I decoy to inhibitory receptors
- C. It prevents interferon secretion by infected cells
- D. It coats the infected cell in host complement regulators
- E. It upregulates activating ligands to exhaust NK cells
Show answer
Correct answer: B
Natural killer cells kill cells that have lost class I, the “missing-self” signal. HCMV restores an inhibitory signal by expressing a class I homologue (UL18) and by supplying a peptide that stabilises HLA-E, both of which engage NK inhibitory receptors. The cell therefore escapes both cytotoxic T cell recognition, through loss of classical class I, and natural killer recognition, through the decoys.

Blocking degranulation, suppressing interferon and recruiting complement regulators are real viral tactics but do not answer missing-self, and upregulating activating ligands would invite NK killing, not prevent it.
Exam-styleDescribe how Epstein-Barr virus establishes lifelong latency and how its latency programmes relate to the EBV-associated malignancies. [6]
Model answer
A complete answer traces the route into the memory B-cell reservoir, then maps the programmes onto the tumours.

Establishing latency. After entry into a B cell (gp350/220 binding CD21), the virus runs its full growth programme (latency III) to drive the cell to proliferate. The infected cell passes through the germinal centre and settles as a resting memory B cell, which expresses essentially no viral genes (latency 0) and so is invisible to the immune system, expressing EBNA1 only when it divides (latency I). This memory B-cell pool is the lifelong reservoir; reactivation to the lytic cycle occurs when such a cell differentiates into a plasma cell.

Mapping programmes to tumours. The programme a tumour runs reflects its origin and its visibility to T cells:
- Latency I (EBNA1 only): Burkitt lymphoma and gastric carcinoma.
- Latency II (adds LMP1 and LMP2): nasopharyngeal carcinoma and Hodgkin lymphoma.
- Latency III (the full growth programme): the lymphomas of immunosuppression, including post-transplant and HIV-associated disease, which can only persist where T-cell control has failed.