Questions

Epstein-Barr virus — Questions

Study questions about Epstein-Barr virus — exam-style, clinical-scenario and FAQ.

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.

40 questions: 30 MCQ, 10 written.

High-priority (past-paper) questions only

Why C

Both 2022 systems (the World Health Organization 5th edition and the International Consensus Classification) stopped treating PTLD as its own disease and folded it into one larger family: lymphoid proliferations and lymphomas arising in the setting of immune deficiency and dysregulation. The reasoning is that the same lesions, with the same EBV biology, appear wherever immune control is lost (inherited immune defects, HIV, transplant, autoimmune disease, drugs, and the immune senescence of age), so they are classified once by shared biology.

Nothing histological is lost (the standalone four-category option describes the older scheme): the familiar categories survive, but each lesion now carries a three-part name (histology, virus, and immune setting). PTLD is not chronic active EBV infection, a reactive hyperplasia, or a Hodgkin subtype.

Why B

The functional framework splits the spectrum into quintessential, EBV-driven PTLD (reactive hyperplasia through to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) and post-transplant lymphoma (a true lymphoma that behaves as it would in an immunocompetent patient and needs lymphoma-directed treatment).

EBV-negativity is the principal warning sign for the second group: EBV-negative disease tends to arise late, be monomorphic, and behave aggressively. The other options point the opposite way: EBV-positivity, polyclonality and early onset all favour quintessential disease, and tonsillar enlargement is a feature of reactive, non-destructive lesions.

Why B

The diagnosis of PTLD is histological. It needs a tissue biopsy (preferably a generous excisional biopsy) characterised by morphology, immunophenotype (including CD20 status, which decides whether rituximab can be used), EBV-encoded RNA (EBER) in-situ hybridisation for EBV, and clonality studies.

Blood tests cannot make the diagnosis: a high or rising EBV-DNA load is only suggestive, a normal load does not fully exclude disease, and serology merely shows past exposure. Imaging localises and stages disease but does not characterise it. The blood load raises suspicion; the biopsy settles it.

Why C

Reducing immunosuppression is the foundation of treatment for every subtype, because it gives the patient back the EBV-specific T cells that immunosuppression had removed. Early, EBV-driven, low-burden disease often responds to this alone.

The other options are later rungs on the graded ladder: rituximab is added for CD20-positive disease, chemotherapy (such as rituximab with CHOP) is reserved for disease that does not respond or for true post-transplant lymphomas, and EBV-specific T cells are used in EBV-positive disease, especially after stem-cell transplant. Antivirals have no role in treating established PTLD, because the latent virus offers them nothing to act on.

Why B

In solid-organ transplant the seronegative recipient of a seropositive organ (donor positive, recipient negative) is at highest risk. Such a recipient meets EBV for the first time, a primary infection, while immunosuppressed and with no EBV-specific T cells to contain it. This is why PTLD falls disproportionately on children, who are most often EBV-naive at transplant.

The other combinations carry lower risk because the recipient already has EBV-specific memory T cells, or because a seronegative organ transmits no virus. Serostatus is one of the strongest single predictors, so the claim that it is irrelevant is wrong. (The high-risk combination reverses in stem-cell transplant, where the graft is the new immune system.)

A complete answer recognises the high-risk setting, works through diagnosis and staging, keeps the differential in mind, and sets out a graded management plan.

Recognise the setting

This is the highest-risk solid-organ scenario: an EBV-naive child (recipient negative) receiving a seropositive organ, now undergoing a primary EBV infection while immunosuppressed, in the first-year window when EBV-positive PTLD is most likely. The rising load and new lymphadenopathy should be treated as possible PTLD until proven otherwise.

Diagnosis and staging

Confirm and trend the EBV-DNA load, and take a focused history and examination. Definitive diagnosis needs tissue: an excisional lymph-node biopsy with histology, immunophenotype (including CD20), EBER staining and clonality, to place the lesion on the spectrum. Stage with cross-sectional imaging (with metabolic imaging where available), assess graft function, and add bone-marrow or central-nervous-system assessment if indicated. Supportive findings include a raised lactate dehydrogenase.

Keep the differential in mind

Fever and lymphadenopathy in a transplant child also raise infection and, where the graft is involved, rejection, and these can coexist with PTLD.

Management

Begin with reduction of immunosuppression, the foundation in a kidney recipient because the graft can, if necessary, be supported by dialysis. If the disease is CD20-positive and does not regress, add rituximab, and escalate to chemotherapy only if it fails or the histology is a true lymphoma. Manage jointly with oncology and the transplant team. Pre-emptive reduction of immunosuppression or rituximab on a rising load is also used in this high-risk group to prevent progression.

A complete answer covers the pathogenesis, the stem-cell-specific risk, EBV-DNA monitoring, and the treatment principles.

Pathogenesis

EBV infects B cells for life and, in its latent state, can switch on a growth programme that drives the B cell to proliferate. This is normally controlled by EBV-specific cytotoxic T cells. Transplant immunosuppression targets T cells, removes that surveillance, and lets EBV-driven B cells grow unchecked.

The stem-cell-specific risk

After stem-cell transplant the graft is the new immune system, so the highest-risk patient is a seropositive recipient of a seronegative or T-cell-depleted donor: the recipient carries EBV, but the new donor immunity brings no EBV-specific T cells. Most such PTLD is donor-derived, EBV-positive, and appears within the first year.

Monitoring

High-risk patients undergo EBV-DNA surveillance of the blood, most intensively in the early months. A high or rising load flags risk and can trigger pre-emptive treatment before disease declares itself, though thresholds are not standardised and a load never substitutes for a tissue diagnosis once a lesion is present.

Treatment

The principles are to reduce immunosuppression where graft-versus-host disease allows, give rituximab for CD20-positive disease (including pre-emptively on a rising load), escalate to chemotherapy for disease that does not respond, and, because the disease is EBV-positive, restore immunity with EBV-specific T cells, which are particularly effective in the stem-cell setting. Antivirals have no role against the latent virus.

A complete answer defines PTLD, sets out the older histological categories, explains the 2022 reframing, and adds the practical functional view.

Definition

Post-transplant lymphoproliferative disorder (PTLD) is an overgrowth of lymphocytes, almost always B cells, that arises after transplantation when immunosuppression weakens the T cells that normally control EBV. It is best defined as a spectrum rather than a single disease, running from a reactive, polyclonal hyperplasia, through clonal neoplasia, to frank malignant lymphoma.

The older histological categories

The previous World Health Organization scheme treated PTLD as a standalone entity with four categories: non-destructive (early) lesions, polymorphic PTLD, monomorphic PTLD (usually a diffuse large B-cell lymphoma), and classic Hodgkin lymphoma PTLD. An EBV-encoded RNA (EBER) stain is performed on every case to establish EBV status.

The 2022 change

The 2022 World Health Organization 5th edition and the International Consensus Classification both stopped treating PTLD as its own entity and placed it within a larger family: lymphoid proliferations and lymphomas arising in immune deficiency and dysregulation. The histological categories survive, but each lesion now carries a three-part name: the histological diagnosis, the driving virus (EBV or KSHV/HHV-8), and the immune setting (here, post-transplant, solid organ or bone marrow).

The functional view

In practice the spectrum is read as quintessential, EBV-driven PTLD (reactive hyperplasia to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) versus post-transplant lymphoma (a true lymphoma needing lymphoma-directed treatment), with EBV-negativity the principal warning sign of the latter.

A complete answer states the competing goals, how the spectrum sets intensity, the graded ladder, and the points commonly overlooked.

The two goals

Management balances two aims that often conflict: eradicate the PTLD and preserve the graft. Reducing immunosuppression serves the first but risks the second, and which wins depends on whether the organ can be supported by other means (a failing kidney can return to dialysis; a failing heart cannot).

Let the spectrum set the intensity

Quintessential, EBV-driven PTLD is treated with the lowest-intensity approach that works, escalating only as needed. A post-transplant lymphoma is treated from the start as the corresponding lymphoma would be in an immunocompetent patient.

The graded ladder

Reduce immunosuppression first, for every subtype. Add rituximab for CD20-positive disease. Escalate to chemotherapy (such as rituximab with CHOP, often in a response-guided sequence) for disease that does not respond or for true lymphomas. In EBV-positive disease, especially after stem-cell transplant, restore EBV-specific T cells. Localised complications may need surgery, and central-nervous-system disease is treated as a primary central nervous system lymphoma.

Points commonly overlooked

Antivirals have no role against the latent virus. CD20 status determines whether rituximab can work. A blood EBV-DNA load guides suspicion and tracks response but does not diagnose disease. Newer approaches (agents targeting CD30, antibodies against interleukin-6, and expanding cellular therapies) may broaden the options, but availability differs widely between settings.

A complete answer covers the three viral drivers, the tumours each causes, and the central role of antiretroviral therapy.

Kaposi sarcoma (HHV-8)

Human herpesvirus 8 causes Kaposi sarcoma, violaceous skin and mucosal lesions (characteristically the palate and gingiva) that can involve the gut and lungs, and also primary effusion lymphoma and multicentric Castleman disease. Antiretroviral therapy is first-line for limited disease, with chemotherapy for advanced or visceral disease.

The AIDS lymphomas (EBV)

Epstein-Barr virus drives the AIDS-defining lymphomas: systemic non-Hodgkin lymphoma (diffuse large B-cell, Burkitt and plasmablastic types) and primary central nervous system lymphoma, which is almost always EBV-positive and is distinguished from cerebral toxoplasmosis by EBV DNA in the cerebrospinal fluid and by metabolic imaging. Treatment combines chemotherapy, often with rituximab for systemic disease and high-dose methotrexate for central nervous system disease, with antiretroviral therapy.

Cervical and anal cancer (HPV)

Human papillomavirus causes accelerated cervical and anal intraepithelial neoplasia and a several-fold higher risk of invasive cervical cancer (an AIDS-defining condition) and anal cancer, which is why regular cervical and anal screening is essential.

The common thread

All three are controlled by cell-mediated immunity, so antiretroviral therapy underpins management of each, with tumour-specific treatment added according to the malignancy.

A complete answer covers what the test measures, where it fails, and the rheumatoid-factor pitfall.

What it detects. Heterophile antibodies are immunoglobulin M antibodies produced during Epstein-Barr virus infection that agglutinate red cells of other species (classically sheep or horse). They are not directed against viral antigens themselves, but their appearance is a useful surrogate for acute infection.

Limitations. The test is often negative in young children, can be negative in the first week or two of illness, and gives occasional false positives in lymphoma, liver disease and autoimmune conditions. A negative result therefore does not exclude Epstein-Barr virus, and virus-specific serology is used when the picture is atypical or the heterophile test is unhelpful.

The rheumatoid-factor pitfall. Rheumatoid factor is itself an immunoglobulin M directed against the Fc portion of immunoglobulin G. In immunoglobulin M assays it can bind non-specifically and generate a false-positive immunoglobulin M signal, including a false-positive viral capsid antigen (VCA) immunoglobulin M. Confirming that the immunoglobulin G arm has matured (for instance that Epstein-Barr nuclear antigen (EBNA) immunoglobulin G is present) helps show that an apparent acute result is in fact a past infection.

A complete answer explains what controls EBV, identifies the high-risk combination in each setting, and gives the single reason they differ.

What controls EBV

EBV-infected B cells are held in check by EBV-specific cytotoxic T cells. PTLD risk is highest whenever the virus is present but those specific T cells are absent.

Solid-organ transplant

The patient keeps their own immune system; the organ is what is foreign. The danger is a seronegative recipient receiving a seropositive organ (donor positive, recipient negative), who meets EBV for the first time while immunosuppressed and has no EBV-specific T cells to contain the primary infection.

Stem-cell transplant

Here the logic reverses because the graft becomes the new immune system. The danger is a seropositive recipient given a seronegative or T-cell-depleted graft (donor negative, recipient positive): the recipient already carries EBV, but the incoming donor immunity brings no EBV-specific T cells to control it. Most PTLD after stem-cell transplant is therefore donor-derived, EBV-associated, and appears within the first year.

The single reason

In both cases the high-risk patient is the one with EBV present but no matching T-cell immunity. Because the immune system comes from the recipient in solid-organ transplant but from the donor in stem-cell transplant, the serostatus that creates that mismatch flips.

A complete answer explains the spectrum, the EBV-driven imbalance that produces it, the functional grouping, and how each follows through to treatment intensity.

The spectrum

PTLD is not one disease but a continuum: a reactive, polyclonal hyperplasia at one end (resembling infectious mononucleosis, architecture preserved, no genetic hallmarks of malignancy), a clonal neoplasia in the middle, and a monoclonal malignant lymphoma at the other end. The same label therefore covers lesions of very different behaviour.

What drives progression

Progression reflects the balance between EBV-driven B-cell proliferation and T-cell control of EBV: EBV promotes proliferation, EBV-specific T cells normally restrain it, and immunosuppression removes that restraint. How far a patient progresses depends on how far EBV is driving the disease and how much T-cell control has been lost.

The functional grouping

The functional reading sorts the spectrum into quintessential, EBV-driven PTLD (hyperplasia through EBV-positive large-cell neoplasia) and post-transplant lymphoma (a true lymphoma behaving as in an immunocompetent patient). EBV status is the principal discriminator: EBV-positive disease is more often the controllable, quintessential form; EBV-negative disease raises concern for a true lymphoma.

How this guides management

Treatment intensity follows position on the spectrum. Quintessential disease is treated with the lowest-intensity approach that works, escalating only as needed: reduce immunosuppression, then add rituximab for CD20-positive disease, then chemotherapy if it does not respond. A post-transplant lymphoma is treated from the outset as the matching lymphoma would be in an immunocompetent patient. EBV-positive disease, especially after stem-cell transplant, can also be treated by restoring EBV-specific T cells. Position on the spectrum therefore determines the intensity of treatment.

The intense, itchy maculopapular rash that follows amoxicillin or ampicillin (though not penicillin) during infectious mononucleosis is a non-allergic, immune-mediated phenomenon specific to the illness; it does not mean the patient is allergic to penicillins and does not preclude their later use. It is distinct from the faint, non-itchy rash that around a tenth of patients develop as part of the illness itself.

It is not an immunoglobulin E (IgE)-mediated allergy, a vasculitis or serum sickness, and it is not the viral exanthem.

Antibody to EBNA appears only weeks to months into convalescence and then persists for life, so its absence alongside a positive VCA immunoglobulin M marks a recent, acute primary infection.

Past infection would show VCA immunoglobulin G with EBNA immunoglobulin G positive and VCA immunoglobulin M negative; a susceptible person has no antibodies; reactivation and chronic active disease show EBNA positivity (often with early-antigen antibody), not its absence.

This is classic infectious mononucleosis: fever, exudative pharyngitis, posterior cervical lymphadenopathy, splenomegaly and atypical lymphocytes (reactive T cells, not infected B cells). Epstein-Barr virus is its commonest cause, and a heterophile antibody is usually positive.

Streptococcal pharyngitis gives neither splenomegaly nor atypical lymphocytes; cytomegalovirus causes a heterophile-negative mononucleosis; acute HIV can mimic the picture and should be considered, but is not the usual cause; adenovirus causes pharyngitis without this haematological picture.

Why D

Adoptive therapy with EBV-specific cytotoxic T cells restores the exact immunity that immunosuppression removed: T cells that recognise and kill EBV-infected B cells. It can only work where the tumour is EBV-positive, and it is most effective after stem-cell transplant, where the disease is almost always EBV-driven and donor-derived.

It is therefore not used for EBV-negative disease (which carries no EBV target), is not limited to Hodgkin or CD20-negative subtypes, and is not applicable to all PTLD. Off-the-shelf, third-party EBV-specific T cells are now reaching practice for relapsed or refractory EBV-positive disease, with little risk of graft-versus-host disease.

On a B cell gp42 binds an HLA (human leukocyte antigen) class II molecule as coreceptor, after gp350/220 has attached to CD21, and the gH/gL heterodimer with gB then drives fusion.

This underlies the tropism switch: epithelial cells, which lack CD21, are entered without gp42 (using integrins and other proteins), so virus made in a B cell carries little gp42 and infects epithelium well, while virus made in epithelium carries gp42 and infects B cells well. CD21 is the attachment receptor, not the gp42 coreceptor.

LMP1 behaves as a constitutively active CD40 receptor, signalling without any ligand and without T-cell help, and so drives the survival and proliferation pathway NF-kB. It is the principal transforming protein of Epstein-Barr virus.

The B-cell-receptor mimic is LMP2A, not LMP1; LMP1 does not directly inhibit p53, amplify c-myc or mimic the interleukin-6 receptor.

LMP2A delivers a tonic signal resembling that of the B-cell receptor, keeping the latently infected B cell alive and blocking the differentiation that would otherwise trigger reactivation, so the cell survives without antigen.

The CD40 mimic is LMP1; the bcl-2 homologue is the separate viral protein BHRF1; the episome is tethered by Epstein-Barr nuclear antigen 1 (EBNA1); a viral DNA polymerase belongs to the lytic cycle.

Epstein-Barr virus is a gammaherpesvirus and the prototype of the genus Lymphocryptovirus; its current species name is Lymphocryptovirus humangamma4.

The other human gammaherpesvirus, Kaposi sarcoma-associated herpesvirus, sits in the genus Rhadinovirus. The alphaherpesviruses (herpes simplex, varicella-zoster) and betaherpesviruses (cytomegalovirus, human herpesviruses 6 and 7) are different subfamilies.

The linear double-stranded DNA genome (about 172 kilobases) circularises on entering the cell into a chromatin-coated episome that the viral protein Epstein-Barr nuclear antigen 1 (EBNA1) tethers to the host chromosomes; the host DNA polymerase then replicates it with the cell. It is not integrated.

Integration, a cytoplasmic linear genome, and an RNA provirus made by reverse transcriptase all describe other viruses; a viral DNA polymerase operates in the lytic cycle, not in latency.

Why A

Oral hairy leukoplakia is an Epstein-Barr virus lesion: corrugated white plaques on the lateral border of the tongue that do not rub off. It is harmless but a useful clinical marker of immunosuppression, and it needs no specific treatment, regressing with immune recovery on antiretroviral therapy.

Herpes simplex, cytomegalovirus and human papillomavirus do not cause it, and Candida (a distractor because oral candidiasis is also common in HIV) wipes off and is fungal, not the cause of the adherent plaques of hairy leukoplakia.

Rituximab is an anti-CD20 antibody that depletes the proliferating B cells of PTLD, acting on the host cells rather than on the virus. It is a host-directed therapeutic monoclonal, not a passive antiviral antibody.

It does not neutralise EBV, replace antibody, or boost antiviral immunity.

All forms of Burkitt lymphoma share a translocation that places the c-myc oncogene under the control of an immunoglobulin gene, classically t(8;14), which drives constitutive proliferation. It arises as an off-target accident of the antibody-gene machinery during the germinal-centre reaction.

t(14;18) defines follicular lymphoma, t(9;22) chronic myeloid leukaemia, t(11;14) mantle-cell lymphoma; EBNA2 amplification is not the lesion, though EBV contributes in the endemic form.

Epstein-Barr virus growth-transforms resting B lymphocytes, driving them to proliferate indefinitely as lymphoblastoid cell lines; this immortalising capacity is the basis of its oncogenic potential. In the host it is restrained by EBV-specific T cells, which is why transformation manifests as disease where that control fails.

It does not lyse B cells on contact, does not integrate, is not confined to epithelium, and does not need malaria to grow (malaria is a cofactor for endemic Burkitt lymphoma specifically).

Why A

Cell-free plasma EBV-DNA is more specific for established EBV-positive disease, while whole blood (which also captures virus inside circulating cells) is more sensitive and so better for surveillance. Many centres therefore use whole blood to screen and plasma to help confirm.

Either sample is acceptable, and both are in routine use, so options C to E are wrong. The deeper point is that neither result diagnoses PTLD: the load raises or lowers suspicion, but tissue biopsy makes the diagnosis, and loads cannot be compared between laboratories because assays differ.

The spleen is enlarged in most cases and can rupture, spontaneously or after minor trauma, in roughly 0.1% to 0.5% of patients; though rare it is potentially fatal. The standard precaution is to avoid contact and collision sport for several weeks, until the splenomegaly has resolved.

Lifelong exercise restriction is unnecessary, splenectomy is not preventive, bed rest does not change outcome, and antibiotics have no role.

Epstein-Barr virus attaches to B cells when gp350/220 binds CD21, the complement receptor 2 that normally recognises the C3d fragment of complement; gp42 then engages an HLA (human leukocyte antigen) class II molecule as coreceptor.

The other options are receptors used by unrelated viruses: CD4 by HIV, CD46 by measles, ICAM-1 by major-group rhinoviruses, and CD155 by poliovirus.

The major envelope glycoprotein gp350/220 attaches the virus to the B-cell surface by binding complement receptor 2 (CD21).

gp42 then acts as the coreceptor-binding protein, and gB with the gH/gL heterodimer drives membrane fusion. LMP1 is a latent membrane oncoprotein, not a virion attachment protein.

Nasopharyngeal carcinoma is EBV-positive in essentially every tumour cell regardless of geography, and runs the latency II programme (Epstein-Barr nuclear antigen 1 (EBNA1), LMP1, LMP2 and the EBV-encoded small RNAs (EBERs)). It clusters in southern China and in middle-aged men, and plasma EBV DNA and a rising immunoglobulin A (IgA) antibody to the viral capsid antigen track and even precede the tumour.

Latency 0 expresses no proteins and is the resting reservoir; the heterophile test belongs to acute mononucleosis; the c-myc translocation defines Burkitt lymphoma, not nasopharyngeal carcinoma.

Why C

Primary central nervous system lymphoma is almost always EBV-positive, so EBV DNA in the cerebrospinal fluid points to lymphoma rather than toxoplasmosis. Metabolic imaging helps in the same way (the lymphoma is hypermetabolic on positron emission tomography or thallium scanning, whereas toxoplasmosis is not), and brain biopsy resolves remaining doubt.

The other features do not separate the two: both occur at low CD4 counts, both cause focal deficits and constitutional symptoms, and both can appear as enhancing or ring-enhancing mass lesions on imaging.

Why C

The depth of T-cell suppression is the central driver of PTLD, so T-cell-depleting induction (antithymocyte globulin, the historical OKT3) is strongly linked to early disease. Cumulative maintenance immunosuppression, by contrast, drives the late peak.

The other options reduce risk or are neutral: lower drug levels and aggressive tapering lessen the net immunosuppressive burden, and calcineurin-inhibitor withdrawal is used to treat PTLD, not cause it. One agent worth remembering separately is belatacept, which is specifically associated with central-nervous-system PTLD in EBV-seronegative recipients.

Why D

EBV association falls in bands across the spectrum. The reactive and early ends are almost always EBV-positive (non-destructive and polymorphic lesions, over 95 per cent), and classic Hodgkin lymphoma PTLD and the EBV-positive mucocutaneous ulcer are usually positive too.

The monomorphic, lymphoma-like end is more mixed: large B-cell and Burkitt types are often positive, but T/NK-cell, high-grade B-cell and plasma-cell types are frequently EBV-negative (under half). The T/NK-cell lymphomas are therefore the least EBV-associated of the options, and sit at the post-transplant-lymphoma end that needs lymphoma-directed treatment.

A large prospective cohort found that Epstein-Barr virus infection raised the later risk of multiple sclerosis around thirtyfold, with a marker of nerve injury rising only after EBV seroconversion, and multiple sclerosis is very rare in the EBV-seronegative. EBV is therefore regarded as a necessary cause, though not a sufficient one, since most infected people never develop the disease. The leading mechanism is molecular mimicry, the immune response to Epstein-Barr nuclear antigen 1 (EBNA1) cross-reacting with a central nervous system protein.

The other options reverse or misstate this relationship.

In latency the genome persists as a quiet episome expressing only a restricted set of genes, with no virus produced; this is the state of the lifelong memory B-cell reservoir. The lytic cycle, triggered by the immediate-early proteins BZLF1 and BRLF1, runs the full gene cascade, builds virions, kills the cell and sheds virus into the saliva.

The other options reverse these features.

Why E

Aciclovir and ganciclovir must be activated by a viral thymidine kinase, which is made only when EBV is replicating (the lytic cycle). The proliferating B cells of PTLD carry EBV in its latent state: the virus is not replicating and makes no thymidine kinase, so the drugs are never activated and have nothing to act on.

This is why antivirals do not treat established disease, although they show a weak signal for prevention (where some lytic replication may be targetable). The drugs are not expelled by the cells, not intrinsically resistant, and not specific to cytomegalovirus.

Aciclovir and its relatives act only on the virus’s lytic replication. By the time mononucleosis presents the viral load has already peaked, and the symptoms are driven by the host T-cell response, not by ongoing viral replication. So antiviral treatment reduces oropharyngeal shedding but shortens neither the illness nor its course.

Epstein-Barr virus is a herpesvirus and is susceptible to aciclovir-class drugs in its lytic phase; the limitation is the immune-mediated nature of the disease, not drug resistance or absorption.

A complete answer states how central nervous system PTLD is treated and the reason it cannot simply follow the usual ladder.

The approach

PTLD in the central nervous system is treated on the lines of a primary central nervous system lymphoma, using regimens designed to reach the brain (high-central-nervous-system-penetrating, methotrexate-based therapy, with radiotherapy or rituximab as appropriate), alongside reduced immunosuppression.

Why it differs

Most of the chemotherapy used for systemic PTLD does not cross the blood-brain barrier in useful concentrations, so standard systemic regimens leave central nervous system disease undertreated. Central nervous system involvement is also a recognised adverse prognostic feature, which reinforces the need for a dedicated, brain-directed strategy rather than the systemic ladder alone.

A complete answer links the virus, the malaria cofactor and the genetic lesion, and gives the clinical picture.

The virus. Endemic Burkitt lymphoma is almost universally EBV-positive, the tumour cells showing the most restricted (latency I) programme, with Epstein-Barr nuclear antigen 1 (EBNA1) only.

The malaria cofactor. It maps to the equatorial-African belt of intense Plasmodium falciparum malaria. Chronic malaria drives polyclonal B-cell proliferation, raises the activity of the antibody-gene-editing enzymes, and weakens EBV-specific T-cell control, all of which expand the pool of infected, dividing B cells in which a transforming accident can occur.

The lesion and clinical picture. That accident is the c-myc translocation, classically t(8;14). The result is the commonest childhood cancer of the region, presenting characteristically as a rapidly growing jaw or orbital tumour.

High priorityMCQ
In the 2022 WHO and International Consensus classifications, how is PTLD now categorised?
- A. As a standalone entity with four categories
- B. As a form of chronic active EBV infection
- C. Within the immune deficiency and dysregulation family
- D. Among the reactive nodal hyperplasias
- E. As a subtype of classic Hodgkin lymphoma
Show answer
Correct answer: C
Why C

Both 2022 systems (the World Health Organization 5th edition and the International Consensus Classification) stopped treating PTLD as its own disease and folded it into one larger family: lymphoid proliferations and lymphomas arising in the setting of immune deficiency and dysregulation. The reasoning is that the same lesions, with the same EBV biology, appear wherever immune control is lost (inherited immune defects, HIV, transplant, autoimmune disease, drugs, and the immune senescence of age), so they are classified once by shared biology.

Nothing histological is lost (the standalone four-category option describes the older scheme): the familiar categories survive, but each lesion now carries a three-part name (histology, virus, and immune setting). PTLD is not chronic active EBV infection, a reactive hyperplasia, or a Hodgkin subtype.
High priorityMCQ
In the functional view of PTLD, which feature most suggests a post-transplant lymphoma rather than quintessential, EBV-driven PTLD?
- A. EBV-positive status
- B. EBV-negative status
- C. Polyclonal proliferation
- D. Early onset after transplant
- E. Tonsillar enlargement
Show answer
Correct answer: B
Why B

The functional framework splits the spectrum into quintessential, EBV-driven PTLD (reactive hyperplasia through to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) and post-transplant lymphoma (a true lymphoma that behaves as it would in an immunocompetent patient and needs lymphoma-directed treatment).

EBV-negativity is the principal warning sign for the second group: EBV-negative disease tends to arise late, be monomorphic, and behave aggressively. The other options point the opposite way: EBV-positivity, polyclonality and early onset all favour quintessential disease, and tonsillar enlargement is a feature of reactive, non-destructive lesions.
High priorityMCQ
What is required to diagnose established PTLD?
- A. A high blood EBV-DNA load alone
- B. Tissue biopsy with histology and EBER
- C. A rising EBV-DNA trend over time
- D. EBV serology indicating past infection
- E. Imaging showing an enlarging mass
Show answer
Correct answer: B
Why B

The diagnosis of PTLD is histological. It needs a tissue biopsy (preferably a generous excisional biopsy) characterised by morphology, immunophenotype (including CD20 status, which decides whether rituximab can be used), EBV-encoded RNA (EBER) in-situ hybridisation for EBV, and clonality studies.

Blood tests cannot make the diagnosis: a high or rising EBV-DNA load is only suggestive, a normal load does not fully exclude disease, and serology merely shows past exposure. Imaging localises and stages disease but does not characterise it. The blood load raises suspicion; the biopsy settles it.
High priorityMCQ
What is the first-line treatment for most PTLD, whatever the subtype?
- A. R-CHOP chemotherapy
- B. Rituximab monotherapy
- C. Reducing immunosuppression
- D. EBV-specific T cells
- E. Antiviral therapy
Show answer
Correct answer: C
Why C

Reducing immunosuppression is the foundation of treatment for every subtype, because it gives the patient back the EBV-specific T cells that immunosuppression had removed. Early, EBV-driven, low-burden disease often responds to this alone.

The other options are later rungs on the graded ladder: rituximab is added for CD20-positive disease, chemotherapy (such as rituximab with CHOP) is reserved for disease that does not respond or for true post-transplant lymphomas, and EBV-specific T cells are used in EBV-positive disease, especially after stem-cell transplant. Antivirals have no role in treating established PTLD, because the latent virus offers them nothing to act on.
High priorityMCQ
Which solid-organ transplant recipient is at highest risk of PTLD?
- A. EBV-seropositive recipient of a seropositive organ
- B. EBV-seronegative recipient of a seropositive organ
- C. EBV-seropositive recipient of a seronegative organ
- D. EBV-seronegative recipient of a seronegative organ
- E. Risk is independent of EBV serostatus
Show answer
Correct answer: B
Why B

In solid-organ transplant the seronegative recipient of a seropositive organ (donor positive, recipient negative) is at highest risk. Such a recipient meets EBV for the first time, a primary infection, while immunosuppressed and with no EBV-specific T cells to contain it. This is why PTLD falls disproportionately on children, who are most often EBV-naive at transplant.

The other combinations carry lower risk because the recipient already has EBV-specific memory T cells, or because a seronegative organ transmits no virus. Serostatus is one of the strongest single predictors, so the claim that it is irrelevant is wrong. (The high-risk combination reverses in stem-cell transplant, where the graft is the new immune system.)
High priorityClinical scenarioA child several months after an EBV-mismatched (donor-positive, recipient-negative) kidney transplant presents with fever, cervical lymphadenopathy and a rising blood EBV-DNA load. Discuss your approach to diagnosis and management. [10]
Model answer
A complete answer recognises the high-risk setting, works through diagnosis and staging, keeps the differential in mind, and sets out a graded management plan.

Recognise the setting

This is the highest-risk solid-organ scenario: an EBV-naive child (recipient negative) receiving a seropositive organ, now undergoing a primary EBV infection while immunosuppressed, in the first-year window when EBV-positive PTLD is most likely. The rising load and new lymphadenopathy should be treated as possible PTLD until proven otherwise.

Diagnosis and staging

Confirm and trend the EBV-DNA load, and take a focused history and examination. Definitive diagnosis needs tissue: an excisional lymph-node biopsy with histology, immunophenotype (including CD20), EBER staining and clonality, to place the lesion on the spectrum. Stage with cross-sectional imaging (with metabolic imaging where available), assess graft function, and add bone-marrow or central-nervous-system assessment if indicated. Supportive findings include a raised lactate dehydrogenase.

Keep the differential in mind

Fever and lymphadenopathy in a transplant child also raise infection and, where the graft is involved, rejection, and these can coexist with PTLD.

Management

Begin with reduction of immunosuppression, the foundation in a kidney recipient because the graft can, if necessary, be supported by dialysis. If the disease is CD20-positive and does not regress, add rituximab, and escalate to chemotherapy only if it fails or the histology is a true lymphoma. Manage jointly with oncology and the transplant team. Pre-emptive reduction of immunosuppression or rituximab on a rising load is also used in this high-risk group to prevent progression.
High priorityExam-styleA patient develops PTLD after allogeneic stem-cell transplantation. Discuss the pathogenesis of EBV-driven PTLD and the principles of monitoring and treatment. [10]
Model answer
A complete answer covers the pathogenesis, the stem-cell-specific risk, EBV-DNA monitoring, and the treatment principles.

Pathogenesis

EBV infects B cells for life and, in its latent state, can switch on a growth programme that drives the B cell to proliferate. This is normally controlled by EBV-specific cytotoxic T cells. Transplant immunosuppression targets T cells, removes that surveillance, and lets EBV-driven B cells grow unchecked.

The stem-cell-specific risk

After stem-cell transplant the graft is the new immune system, so the highest-risk patient is a seropositive recipient of a seronegative or T-cell-depleted donor: the recipient carries EBV, but the new donor immunity brings no EBV-specific T cells. Most such PTLD is donor-derived, EBV-positive, and appears within the first year.

Monitoring

High-risk patients undergo EBV-DNA surveillance of the blood, most intensively in the early months. A high or rising load flags risk and can trigger pre-emptive treatment before disease declares itself, though thresholds are not standardised and a load never substitutes for a tissue diagnosis once a lesion is present.

Treatment

The principles are to reduce immunosuppression where graft-versus-host disease allows, give rituximab for CD20-positive disease (including pre-emptively on a rising load), escalate to chemotherapy for disease that does not respond, and, because the disease is EBV-positive, restore immunity with EBV-specific T cells, which are particularly effective in the stem-cell setting. Antivirals have no role against the latent virus.
High priorityExam-styleDefine post-transplant lymphoproliferative disorder, and outline how it is classified, including the change introduced in 2022. [8]
Model answer
A complete answer defines PTLD, sets out the older histological categories, explains the 2022 reframing, and adds the practical functional view.

Definition

Post-transplant lymphoproliferative disorder (PTLD) is an overgrowth of lymphocytes, almost always B cells, that arises after transplantation when immunosuppression weakens the T cells that normally control EBV. It is best defined as a spectrum rather than a single disease, running from a reactive, polyclonal hyperplasia, through clonal neoplasia, to frank malignant lymphoma.

The older histological categories

The previous World Health Organization scheme treated PTLD as a standalone entity with four categories: non-destructive (early) lesions, polymorphic PTLD, monomorphic PTLD (usually a diffuse large B-cell lymphoma), and classic Hodgkin lymphoma PTLD. An EBV-encoded RNA (EBER) stain is performed on every case to establish EBV status.

The 2022 change

The 2022 World Health Organization 5th edition and the International Consensus Classification both stopped treating PTLD as its own entity and placed it within a larger family: lymphoid proliferations and lymphomas arising in immune deficiency and dysregulation. The histological categories survive, but each lesion now carries a three-part name: the histological diagnosis, the driving virus (EBV or KSHV/HHV-8), and the immune setting (here, post-transplant, solid organ or bone marrow).

The functional view

In practice the spectrum is read as quintessential, EBV-driven PTLD (reactive hyperplasia to EBV-positive large-cell neoplasia, much of it controllable with low-intensity treatment) versus post-transplant lymphoma (a true lymphoma needing lymphoma-directed treatment), with EBV-negativity the principal warning sign of the latter.
High priorityExam-styleDiscuss the principles of managing established PTLD. [10]
Model answer
A complete answer states the competing goals, how the spectrum sets intensity, the graded ladder, and the points commonly overlooked.

The two goals

Management balances two aims that often conflict: eradicate the PTLD and preserve the graft. Reducing immunosuppression serves the first but risks the second, and which wins depends on whether the organ can be supported by other means (a failing kidney can return to dialysis; a failing heart cannot).

Let the spectrum set the intensity

Quintessential, EBV-driven PTLD is treated with the lowest-intensity approach that works, escalating only as needed. A post-transplant lymphoma is treated from the start as the corresponding lymphoma would be in an immunocompetent patient.

The graded ladder

Reduce immunosuppression first, for every subtype. Add rituximab for CD20-positive disease. Escalate to chemotherapy (such as rituximab with CHOP, often in a response-guided sequence) for disease that does not respond or for true lymphomas. In EBV-positive disease, especially after stem-cell transplant, restore EBV-specific T cells. Localised complications may need surgery, and central-nervous-system disease is treated as a primary central nervous system lymphoma.

Points commonly overlooked

Antivirals have no role against the latent virus. CD20 status determines whether rituximab can work. A blood EBV-DNA load guides suspicion and tracks response but does not diagnose disease. Newer approaches (agents targeting CD30, antibodies against interleukin-6, and expanding cellular therapies) may broaden the options, but availability differs widely between settings.
High priorityExam-styleDiscuss the virus-associated malignancies seen in AIDS. [8]
Model answer
A complete answer covers the three viral drivers, the tumours each causes, and the central role of antiretroviral therapy.

Kaposi sarcoma (HHV-8)

Human herpesvirus 8 causes Kaposi sarcoma, violaceous skin and mucosal lesions (characteristically the palate and gingiva) that can involve the gut and lungs, and also primary effusion lymphoma and multicentric Castleman disease. Antiretroviral therapy is first-line for limited disease, with chemotherapy for advanced or visceral disease.

The AIDS lymphomas (EBV)

Epstein-Barr virus drives the AIDS-defining lymphomas: systemic non-Hodgkin lymphoma (diffuse large B-cell, Burkitt and plasmablastic types) and primary central nervous system lymphoma, which is almost always EBV-positive and is distinguished from cerebral toxoplasmosis by EBV DNA in the cerebrospinal fluid and by metabolic imaging. Treatment combines chemotherapy, often with rituximab for systemic disease and high-dose methotrexate for central nervous system disease, with antiretroviral therapy.

Cervical and anal cancer (HPV)

Human papillomavirus causes accelerated cervical and anal intraepithelial neoplasia and a several-fold higher risk of invasive cervical cancer (an AIDS-defining condition) and anal cancer, which is why regular cervical and anal screening is essential.

The common thread

All three are controlled by cell-mediated immunity, so antiretroviral therapy underpins management of each, with tumour-specific treatment added according to the malignancy.
High priorityExam-styleExplain the heterophile antibody (Paul-Bunnell or Monospot) test in infectious mononucleosis: what it detects, its limitations, and how rheumatoid factor can cause a false-positive immunoglobulin M result. [6]
Model answer
A complete answer covers what the test measures, where it fails, and the rheumatoid-factor pitfall.

What it detects. Heterophile antibodies are immunoglobulin M antibodies produced during Epstein-Barr virus infection that agglutinate red cells of other species (classically sheep or horse). They are not directed against viral antigens themselves, but their appearance is a useful surrogate for acute infection.

Limitations. The test is often negative in young children, can be negative in the first week or two of illness, and gives occasional false positives in lymphoma, liver disease and autoimmune conditions. A negative result therefore does not exclude Epstein-Barr virus, and virus-specific serology is used when the picture is atypical or the heterophile test is unhelpful.

The rheumatoid-factor pitfall. Rheumatoid factor is itself an immunoglobulin M directed against the Fc portion of immunoglobulin G. In immunoglobulin M assays it can bind non-specifically and generate a false-positive immunoglobulin M signal, including a false-positive viral capsid antigen (VCA) immunoglobulin M. Confirming that the immunoglobulin G arm has matured (for instance that Epstein-Barr nuclear antigen (EBNA) immunoglobulin G is present) helps show that an apparent acute result is in fact a past infection.
High priorityExam-styleWhy does the highest-risk EBV serostatus combination for PTLD reverse between solid-organ and stem-cell transplantation? [5]
Model answer
A complete answer explains what controls EBV, identifies the high-risk combination in each setting, and gives the single reason they differ.

What controls EBV

EBV-infected B cells are held in check by EBV-specific cytotoxic T cells. PTLD risk is highest whenever the virus is present but those specific T cells are absent.

Solid-organ transplant

The patient keeps their own immune system; the organ is what is foreign. The danger is a seronegative recipient receiving a seropositive organ (donor positive, recipient negative), who meets EBV for the first time while immunosuppressed and has no EBV-specific T cells to contain the primary infection.

Stem-cell transplant

Here the logic reverses because the graft becomes the new immune system. The danger is a seropositive recipient given a seronegative or T-cell-depleted graft (donor negative, recipient positive): the recipient already carries EBV, but the incoming donor immunity brings no EBV-specific T cells to control it. Most PTLD after stem-cell transplant is therefore donor-derived, EBV-associated, and appears within the first year.

The single reason

In both cases the high-risk patient is the one with EBV present but no matching T-cell immunity. Because the immune system comes from the recipient in solid-organ transplant but from the donor in stem-cell transplant, the serostatus that creates that mismatch flips.
High priorityExam-styleWhy is PTLD best understood as a spectrum rather than a single disease, and how does that understanding guide management? [10]
Model answer
A complete answer explains the spectrum, the EBV-driven imbalance that produces it, the functional grouping, and how each follows through to treatment intensity.

The spectrum

PTLD is not one disease but a continuum: a reactive, polyclonal hyperplasia at one end (resembling infectious mononucleosis, architecture preserved, no genetic hallmarks of malignancy), a clonal neoplasia in the middle, and a monoclonal malignant lymphoma at the other end. The same label therefore covers lesions of very different behaviour.

What drives progression

Progression reflects the balance between EBV-driven B-cell proliferation and T-cell control of EBV: EBV promotes proliferation, EBV-specific T cells normally restrain it, and immunosuppression removes that restraint. How far a patient progresses depends on how far EBV is driving the disease and how much T-cell control has been lost.

The functional grouping

The functional reading sorts the spectrum into quintessential, EBV-driven PTLD (hyperplasia through EBV-positive large-cell neoplasia) and post-transplant lymphoma (a true lymphoma behaving as in an immunocompetent patient). EBV status is the principal discriminator: EBV-positive disease is more often the controllable, quintessential form; EBV-negative disease raises concern for a true lymphoma.

How this guides management

Treatment intensity follows position on the spectrum. Quintessential disease is treated with the lowest-intensity approach that works, escalating only as needed: reduce immunosuppression, then add rituximab for CD20-positive disease, then chemotherapy if it does not respond. A post-transplant lymphoma is treated from the outset as the matching lymphoma would be in an immunocompetent patient. EBV-positive disease, especially after stem-cell transplant, can also be treated by restoring EBV-specific T cells. Position on the spectrum therefore determines the intensity of treatment.
MCQ
A patient with infectious mononucleosis is given amoxicillin and develops a widespread maculopapular rash. What does this rash represent?
- A. An IgE-mediated type I penicillin allergy
- B. A drug-induced small-vessel vasculitis
- C. The viral exanthem of EBV itself
- D. A non-allergic rash of mononucleosis
- E. A serum-sickness reaction to penicillin
Show answer
Correct answer: D
The intense, itchy maculopapular rash that follows amoxicillin or ampicillin (though not penicillin) during infectious mononucleosis is a non-allergic, immune-mediated phenomenon specific to the illness; it does not mean the patient is allergic to penicillins and does not preclude their later use. It is distinct from the faint, non-itchy rash that around a tenth of patients develop as part of the illness itself.

It is not an immunoglobulin E (IgE)-mediated allergy, a vasculitis or serum sickness, and it is not the viral exanthem.
MCQ
A patient's EBV serology shows viral capsid antigen (VCA) immunoglobulin M positive, VCA immunoglobulin G positive, and Epstein-Barr nuclear antigen (EBNA) immunoglobulin G negative. How is this interpreted?
- A. Past infection, immune
- B. Uninfected, susceptible
- C. Reactivation of latent EBV
- D. Chronic active EBV infection
- E. Acute primary infection
Show answer
Correct answer: E
Antibody to EBNA appears only weeks to months into convalescence and then persists for life, so its absence alongside a positive VCA immunoglobulin M marks a recent, acute primary infection.

Past infection would show VCA immunoglobulin G with EBNA immunoglobulin G positive and VCA immunoglobulin M negative; a susceptible person has no antibodies; reactivation and chronic active disease show EBNA positivity (often with early-antigen antibody), not its absence.
MCQ
An 18-year-old has a week of fever, an exudative pharyngitis, tender posterior cervical lymph nodes and a palpable spleen, with many atypical lymphocytes on the blood film. What is the most likely cause?
- A. Streptococcal pharyngitis
- B. Epstein-Barr virus
- C. Cytomegalovirus
- D. Acute HIV infection
- E. Adenovirus
Show answer
Correct answer: B
This is classic infectious mononucleosis: fever, exudative pharyngitis, posterior cervical lymphadenopathy, splenomegaly and atypical lymphocytes (reactive T cells, not infected B cells). Epstein-Barr virus is its commonest cause, and a heterophile antibody is usually positive.

Streptococcal pharyngitis gives neither splenomegaly nor atypical lymphocytes; cytomegalovirus causes a heterophile-negative mononucleosis; acute HIV can mimic the picture and should be considered, but is not the usual cause; adenovirus causes pharyngitis without this haematological picture.
MCQ
EBV-specific cytotoxic T-cell therapy is appropriate for which PTLD?
- A. EBV-negative monomorphic disease
- B. All PTLD regardless of EBV status
- C. Classic Hodgkin lymphoma PTLD only
- D. EBV-positive disease, mainly after stem-cell transplant
- E. Only CD20-negative disease
Show answer
Correct answer: D
Why D

Adoptive therapy with EBV-specific cytotoxic T cells restores the exact immunity that immunosuppression removed: T cells that recognise and kill EBV-infected B cells. It can only work where the tumour is EBV-positive, and it is most effective after stem-cell transplant, where the disease is almost always EBV-driven and donor-derived.

It is therefore not used for EBV-negative disease (which carries no EBV target), is not limited to Hodgkin or CD20-negative subtypes, and is not applicable to all PTLD. Off-the-shelf, third-party EBV-specific T cells are now reaching practice for relapsed or refractory EBV-positive disease, with little risk of graft-versus-host disease.
MCQ
Epstein-Barr virus glycoprotein gp42 engages which molecule as the coreceptor for entry into B cells?
- A. CD21 (complement receptor 2)
- B. An integrin of the avb6 type
- C. Sialylated surface glycans
- D. The CD4 molecule
- E. An HLA class II molecule
Show answer
Correct answer: E
On a B cell gp42 binds an HLA (human leukocyte antigen) class II molecule as coreceptor, after gp350/220 has attached to CD21, and the gH/gL heterodimer with gB then drives fusion.

This underlies the tropism switch: epithelial cells, which lack CD21, are entered without gp42 (using integrins and other proteins), so virus made in a B cell carries little gp42 and infects epithelium well, while virus made in epithelium carries gp42 and infects B cells well. CD21 is the attachment receptor, not the gp42 coreceptor.
MCQ
How does the Epstein-Barr virus protein LMP1 transform B cells?
- A. As a B-cell-receptor mimic that drives survival
- B. By directly inhibiting p53
- C. By directly amplifying c-myc
- D. As a constitutively active CD40 mimic
- E. As an interleukin-6 receptor mimic
Show answer
Correct answer: D
LMP1 behaves as a constitutively active CD40 receptor, signalling without any ligand and without T-cell help, and so drives the survival and proliferation pathway NF-kB. It is the principal transforming protein of Epstein-Barr virus.

The B-cell-receptor mimic is LMP2A, not LMP1; LMP1 does not directly inhibit p53, amplify c-myc or mimic the interleukin-6 receptor.
MCQ
How does the Epstein-Barr virus protein LMP2A help the virus persist in B cells?
- A. By mimicking CD40 signalling
- B. By encoding a viral DNA polymerase
- C. By acting as a viral bcl-2 homologue
- D. By mimicking B-cell-receptor signals
- E. By tethering the episome to chromatin
Show answer
Correct answer: D
LMP2A delivers a tonic signal resembling that of the B-cell receptor, keeping the latently infected B cell alive and blocking the differentiation that would otherwise trigger reactivation, so the cell survives without antigen.

The CD40 mimic is LMP1; the bcl-2 homologue is the separate viral protein BHRF1; the episome is tethered by Epstein-Barr nuclear antigen 1 (EBNA1); a viral DNA polymerase belongs to the lytic cycle.
MCQ
How is Epstein-Barr virus classified?
- A. Alphaherpesvirus, genus Simplexvirus
- B. Betaherpesvirus, genus Cytomegalovirus
- C. Gammaherpesvirus, genus Lymphocryptovirus
- D. Gammaherpesvirus, genus Rhadinovirus
- E. Alphaherpesvirus, genus Varicellovirus
Show answer
Correct answer: C
Epstein-Barr virus is a gammaherpesvirus and the prototype of the genus Lymphocryptovirus; its current species name is Lymphocryptovirus humangamma4.

The other human gammaherpesvirus, Kaposi sarcoma-associated herpesvirus, sits in the genus Rhadinovirus. The alphaherpesviruses (herpes simplex, varicella-zoster) and betaherpesviruses (cytomegalovirus, human herpesviruses 6 and 7) are different subfamilies.
MCQ
How is the Epstein-Barr virus genome maintained in a latently infected cell?
- A. Integrated into a host chromosome
- B. As a circular episome tethered by EBNA1
- C. As linear DNA free in the cytoplasm
- D. As an RNA provirus made by reverse transcriptase
- E. Copied continuously by a viral DNA polymerase
Show answer
Correct answer: B
The linear double-stranded DNA genome (about 172 kilobases) circularises on entering the cell into a chromatin-coated episome that the viral protein Epstein-Barr nuclear antigen 1 (EBNA1) tethers to the host chromosomes; the host DNA polymerase then replicates it with the cell. It is not integrated.

Integration, a cytoplasmic linear genome, and an RNA provirus made by reverse transcriptase all describe other viruses; a viral DNA polymerase operates in the lytic cycle, not in latency.
MCQ
Oral hairy leukoplakia in a patient with HIV is caused by which virus?
- A. Epstein-Barr virus
- B. Herpes simplex virus
- C. Human papillomavirus
- D. Cytomegalovirus
- E. Candida albicans
Show answer
Correct answer: A
Why A

Oral hairy leukoplakia is an Epstein-Barr virus lesion: corrugated white plaques on the lateral border of the tongue that do not rub off. It is harmless but a useful clinical marker of immunosuppression, and it needs no specific treatment, regressing with immune recovery on antiretroviral therapy.

Herpes simplex, cytomegalovirus and human papillomavirus do not cause it, and Candida (a distractor because oral candidiasis is also common in HIV) wipes off and is fungal, not the cause of the adherent plaques of hairy leukoplakia.
MCQ
Rituximab is used in EBV-driven post-transplant lymphoproliferative disorder (PTLD) because it:
- A. Neutralises circulating EBV particles
- B. Replaces missing antibody in the patient
- C. Boosts the patient's own EBV immunity
- D. Provides passive neutralising antibody against EBV
- E. Depletes the proliferating CD20-positive B cells
Show answer
Correct answer: E
Rituximab is an anti-CD20 antibody that depletes the proliferating B cells of PTLD, acting on the host cells rather than on the virus. It is a host-directed therapeutic monoclonal, not a passive antiviral antibody.

It does not neutralise EBV, replace antibody, or boost antiviral immunity.
MCQ
What is the defining genetic lesion of Burkitt lymphoma?
- A. t(14;18) involving the BCL2 anti-apoptosis gene
- B. t(8;14), c-myc under immunoglobulin control
- C. t(9;22) producing BCR-ABL1
- D. t(11;14) involving cyclin D1
- E. Amplification of the EBNA2 gene
Show answer
Correct answer: B
All forms of Burkitt lymphoma share a translocation that places the c-myc oncogene under the control of an immunoglobulin gene, classically t(8;14), which drives constitutive proliferation. It arises as an off-target accident of the antibody-gene machinery during the germinal-centre reaction.

t(14;18) defines follicular lymphoma, t(9;22) chronic myeloid leukaemia, t(11;14) mantle-cell lymphoma; EBNA2 amplification is not the lesion, though EBV contributes in the endemic form.
MCQ
What is the defining property of Epstein-Barr virus when it infects B cells in culture?
- A. It lyses the B cells within hours
- B. It integrates into the T-cell genome
- C. It immortalises B cells indefinitely
- D. It replicates only in epithelial cells
- E. It requires malaria co-infection to grow
Show answer
Correct answer: C
Epstein-Barr virus growth-transforms resting B lymphocytes, driving them to proliferate indefinitely as lymphoblastoid cell lines; this immortalising capacity is the basis of its oncogenic potential. In the host it is restrained by EBV-specific T cells, which is why transformation manifests as disease where that control fails.

It does not lyse B cells on contact, does not integrate, is not confined to epithelium, and does not need malaria to grow (malaria is a cofactor for endemic Burkitt lymphoma specifically).
MCQ
When monitoring EBV-DNA after transplant, how do plasma and whole-blood testing differ?
- A. Plasma is more specific; whole blood more sensitive
- B. Plasma is more sensitive; whole blood more specific
- C. Both perform identically
- D. Plasma cannot detect EBV-DNA
- E. Whole blood is no longer used
Show answer
Correct answer: A
Why A

Cell-free plasma EBV-DNA is more specific for established EBV-positive disease, while whole blood (which also captures virus inside circulating cells) is more sensitive and so better for surveillance. Many centres therefore use whole blood to screen and plasma to help confirm.

Either sample is acceptable, and both are in routine use, so options C to E are wrong. The deeper point is that neither result diagnoses PTLD: the load raises or lowers suspicion, but tissue biopsy makes the diagnosis, and loads cannot be compared between laboratories because assays differ.
MCQ
Which advice is most important for a young adult recovering from infectious mononucleosis?
- A. Avoid contact sport for several weeks
- B. Lifelong avoidance of all exercise
- C. Early splenectomy to prevent rupture
- D. Strict bed rest until fully recovered
- E. Prophylactic antibiotics for the spleen
Show answer
Correct answer: A
The spleen is enlarged in most cases and can rupture, spontaneously or after minor trauma, in roughly 0.1% to 0.5% of patients; though rare it is potentially fatal. The standard precaution is to avoid contact and collision sport for several weeks, until the splenomegaly has resolved.

Lifelong exercise restriction is unnecessary, splenectomy is not preventive, bed rest does not change outcome, and antibiotics have no role.
MCQ
Which cell-surface molecule is the receptor that Epstein-Barr virus uses to attach to B cells?
- A. CD4 (the T-helper marker)
- B. CD46 (a complement regulator)
- C. ICAM-1 (an adhesion molecule)
- D. CD21 (complement receptor 2)
- E. CD155 (the poliovirus receptor)
Show answer
Correct answer: D
Epstein-Barr virus attaches to B cells when gp350/220 binds CD21, the complement receptor 2 that normally recognises the C3d fragment of complement; gp42 then engages an HLA (human leukocyte antigen) class II molecule as coreceptor.

The other options are receptors used by unrelated viruses: CD4 by HIV, CD46 by measles, ICAM-1 by major-group rhinoviruses, and CD155 by poliovirus.
MCQ
Which Epstein-Barr virus glycoprotein mediates attachment to B cells?
- A. gp350
- B. gp42
- C. gB
- D. gH/gL
- E. LMP1
Show answer
Correct answer: A
The major envelope glycoprotein gp350/220 attaches the virus to the B-cell surface by binding complement receptor 2 (CD21).

gp42 then acts as the coreceptor-binding protein, and gB with the gH/gL heterodimer drives membrane fusion. LMP1 is a latent membrane oncoprotein, not a virion attachment protein.
MCQ
Which feature is characteristic of Epstein-Barr virus-associated nasopharyngeal carcinoma?
- A. Latency 0 with no viral protein expression
- B. A positive heterophile antibody test
- C. Latency II with LMP1 expression
- D. A defining c-myc translocation
- E. Entry driven by gp350 overexpression
Show answer
Correct answer: C
Nasopharyngeal carcinoma is EBV-positive in essentially every tumour cell regardless of geography, and runs the latency II programme (Epstein-Barr nuclear antigen 1 (EBNA1), LMP1, LMP2 and the EBV-encoded small RNAs (EBERs)). It clusters in southern China and in middle-aged men, and plasma EBV DNA and a rising immunoglobulin A (IgA) antibody to the viral capsid antigen track and even precede the tumour.

Latency 0 expresses no proteins and is the resting reservoir; the heterophile test belongs to acute mononucleosis; the c-myc translocation defines Burkitt lymphoma, not nasopharyngeal carcinoma.
MCQ
Which finding best distinguishes primary central nervous system lymphoma from cerebral toxoplasmosis in AIDS?
- A. Multiple ring-enhancing lesions on imaging
- B. A low CD4 count
- C. EBV DNA in cerebrospinal fluid
- D. Focal neurological deficits
- E. Headache and fever
Show answer
Correct answer: C
Why C

Primary central nervous system lymphoma is almost always EBV-positive, so EBV DNA in the cerebrospinal fluid points to lymphoma rather than toxoplasmosis. Metabolic imaging helps in the same way (the lymphoma is hypermetabolic on positron emission tomography or thallium scanning, whereas toxoplasmosis is not), and brain biopsy resolves remaining doubt.

The other features do not separate the two: both occur at low CD4 counts, both cause focal deficits and constitutional symptoms, and both can appear as enhancing or ring-enhancing mass lesions on imaging.
MCQ
Which immunosuppression-related factor is most associated with early-onset PTLD?
- A. Aggressive early steroid tapering
- B. Low maintenance drug levels
- C. T-cell-depleting induction therapy
- D. Calcineurin inhibitor withdrawal
- E. mTOR inhibitor maintenance
Show answer
Correct answer: C
Why C

The depth of T-cell suppression is the central driver of PTLD, so T-cell-depleting induction (antithymocyte globulin, the historical OKT3) is strongly linked to early disease. Cumulative maintenance immunosuppression, by contrast, drives the late peak.

The other options reduce risk or are neutral: lower drug levels and aggressive tapering lessen the net immunosuppressive burden, and calcineurin-inhibitor withdrawal is used to treat PTLD, not cause it. One agent worth remembering separately is belatacept, which is specifically associated with central-nervous-system PTLD in EBV-seronegative recipients.
MCQ
Which PTLD histology is least likely to be EBV-positive?
- A. Non-destructive (hyperplasia) lesions
- B. Polymorphic PTLD
- C. Classic Hodgkin lymphoma PTLD
- D. Monomorphic T/NK-cell lymphoma
- E. EBV-positive mucocutaneous ulcer
Show answer
Correct answer: D
Why D

EBV association falls in bands across the spectrum. The reactive and early ends are almost always EBV-positive (non-destructive and polymorphic lesions, over 95 per cent), and classic Hodgkin lymphoma PTLD and the EBV-positive mucocutaneous ulcer are usually positive too.

The monomorphic, lymphoma-like end is more mixed: large B-cell and Burkitt types are often positive, but T/NK-cell, high-grade B-cell and plasma-cell types are frequently EBV-negative (under half). The T/NK-cell lymphomas are therefore the least EBV-associated of the options, and sit at the post-transplant-lymphoma end that needs lymphoma-directed treatment.
MCQ
Which statement about Epstein-Barr virus and multiple sclerosis is best supported by current evidence?
- A. Prior EBV infection is a near-necessary precursor
- B. EBV vaccination is the established cause of MS
- C. EBV infection is protective against developing MS
- D. EBV causes MS only with cytomegalovirus co-infection
- E. EBV infection is unrelated to later MS risk
Show answer
Correct answer: A
A large prospective cohort found that Epstein-Barr virus infection raised the later risk of multiple sclerosis around thirtyfold, with a marker of nerve injury rising only after EBV seroconversion, and multiple sclerosis is very rare in the EBV-seronegative. EBV is therefore regarded as a necessary cause, though not a sufficient one, since most infected people never develop the disease. The leading mechanism is molecular mimicry, the immune response to Epstein-Barr nuclear antigen 1 (EBNA1) cross-reacting with a central nervous system protein.

The other options reverse or misstate this relationship.
MCQ
Which statement correctly distinguishes Epstein-Barr virus latency from the lytic cycle?
- A. Latency produces infectious virus, the lytic cycle none
- B. Latency expresses few genes and makes no virus
- C. Lytic infection persists silently for life
- D. Latency is driven by the BZLF1 immediate-early protein
- E. The lytic cycle is the lifelong reservoir state
Show answer
Correct answer: B
In latency the genome persists as a quiet episome expressing only a restricted set of genes, with no virus produced; this is the state of the lifelong memory B-cell reservoir. The lytic cycle, triggered by the immediate-early proteins BZLF1 and BRLF1, runs the full gene cascade, builds virions, kills the cell and sheds virus into the saliva.

The other options reverse these features.
MCQ
Why do aciclovir and ganciclovir not treat established PTLD?
- A. The drugs cannot penetrate involved lymph nodes
- B. The tumour cells actively expel the drugs
- C. The virus is intrinsically resistant to both
- D. The drugs act only against cytomegalovirus
- E. Latent virus expresses no thymidine kinase
Show answer
Correct answer: E
Why E

Aciclovir and ganciclovir must be activated by a viral thymidine kinase, which is made only when EBV is replicating (the lytic cycle). The proliferating B cells of PTLD carry EBV in its latent state: the virus is not replicating and makes no thymidine kinase, so the drugs are never activated and have nothing to act on.

This is why antivirals do not treat established disease, although they show a weak signal for prevention (where some lytic replication may be targetable). The drugs are not expelled by the cells, not intrinsically resistant, and not specific to cytomegalovirus.
MCQ
Why does aciclovir not change the clinical course of infectious mononucleosis?
- A. EBV lacks a thymidine kinase to activate it
- B. EBV is not a herpesvirus
- C. The illness is immune-mediated, not lytic
- D. Resistance to aciclovir is universal in EBV
- E. Aciclovir is too poorly absorbed orally
Show answer
Correct answer: C
Aciclovir and its relatives act only on the virus’s lytic replication. By the time mononucleosis presents the viral load has already peaked, and the symptoms are driven by the host T-cell response, not by ongoing viral replication. So antiviral treatment reduces oropharyngeal shedding but shortens neither the illness nor its course.

Epstein-Barr virus is a herpesvirus and is susceptible to aciclovir-class drugs in its lytic phase; the limitation is the immune-mediated nature of the disease, not drug resistance or absorption.
Exam-styleHow is central nervous system PTLD managed, and why does it need a different approach? [5]
Model answer
A complete answer states how central nervous system PTLD is treated and the reason it cannot simply follow the usual ladder.

The approach

PTLD in the central nervous system is treated on the lines of a primary central nervous system lymphoma, using regimens designed to reach the brain (high-central-nervous-system-penetrating, methotrexate-based therapy, with radiotherapy or rituximab as appropriate), alongside reduced immunosuppression.

Why it differs

Most of the chemotherapy used for systemic PTLD does not cross the blood-brain barrier in useful concentrations, so standard systemic regimens leave central nervous system disease undertreated. Central nervous system involvement is also a recognised adverse prognostic feature, which reinforces the need for a dedicated, brain-directed strategy rather than the systemic ladder alone.
Exam-styleOutline the role of Epstein-Barr virus and its cofactors in endemic (African) Burkitt lymphoma. [5]
Model answer
A complete answer links the virus, the malaria cofactor and the genetic lesion, and gives the clinical picture.

The virus. Endemic Burkitt lymphoma is almost universally EBV-positive, the tumour cells showing the most restricted (latency I) programme, with Epstein-Barr nuclear antigen 1 (EBNA1) only.

The malaria cofactor. It maps to the equatorial-African belt of intense Plasmodium falciparum malaria. Chronic malaria drives polyclonal B-cell proliferation, raises the activity of the antibody-gene-editing enzymes, and weakens EBV-specific T-cell control, all of which expand the pool of infected, dividing B cells in which a transforming accident can occur.

The lesion and clinical picture. That accident is the c-myc translocation, classically t(8;14). The result is the commonest childhood cancer of the region, presenting characteristically as a rapidly growing jaw or orbital tumour.