Herpesviruses
Common properties ★★★
| Property | Detail |
|---|---|
| Shape and size | Spherical, 150–200 nm — LARGE |
| Core | Linear double-stranded DNA |
| Capsid | Icosahedral |
| Tegument | The layer between the capsid and the envelope |
| Envelope | Present |
⭐ The chapter summary — three sentences worth memorising
- Herpesviruses are LARGE viruses with a double-stranded DNA genome; about 100 different herpesviruses are known, infecting different species
- ALL herpesviruses establish LIFELONG LATENT infections
- Herpesviruses may cause SEVERE DISEASE in immunocompromised persons
All herpesviruses establish lifelong latent infections. Once you have met one, you never clear it.
This is Unit 20 §4's latent infection — the virus persists in a hiding form producing no infectious virus until a trigger reactivates it. Each member of the family simply chooses a different hiding place:
• HSV-1 — trigeminal ganglia → cold sores
• HSV-2 — sacral ganglia → recurrent genital herpes
• VZV — dorsal root and cranial sensory ganglia → zoster
• EBV — B lymphocytes → reactivation and malignant transformation
• CMV — leukocytes and other cells → disease in transplant and AIDS patients
And point 3 follows from point 2: if everyone carries these viruses for life, held in check by T cells, then losing T-cell function — transplantation, chemotherapy, AIDS — releases them all at once. That is why CMV retinitis, disseminated zoster and EBV-driven lymphoproliferative disease are hallmarks of immunosuppression.
- Describe herpesvirus structure. → Spherical, 150–200 nm, linear dsDNA core, icosahedral capsid, tegument between capsid and envelope, enveloped
- Give the three summary points. → Large dsDNA viruses, about 100 known · ALL establish lifelong latent infection · they cause severe disease in the immunocompromised
- Where does each member hide? → HSV-1 trigeminal ganglia · HSV-2 sacral ganglia · VZV dorsal root and cranial sensory ganglia · EBV B lymphocytes
Herpes simplex virus ★★★
| Detail | |
|---|---|
| Source | Patients, or persons excreting virus |
| Horizontal transmission | Close contact (HSV-1) · respiratory tract (HSV-1) · genital tract (HSV-2) |
| Vertical transmission | Placenta → fetus · birth canal → newborn |
| Types of infection | Primary · LATENT · RECURRENT |
| Latency site | HSV-1 — trigeminal ganglia (recurring as cold sores) · HSV-2 — sacral ganglia |
Unit 20 §1 listed the diseases: HSV-1 causes gingivostomatitis, pharyngitis, herpes labialis (cold sores), genital herpes, encephalitis and keratoconjunctivitis — the deck's own example of one virus causing several different diseases.
| Diagnosis and management | Detail |
|---|---|
| Diagnosis | Cytopathology of scrapings · isolation and identification of virus · molecular detection by PCR · serology (IgM) |
| Vaccine | NO vaccine — subunit and DNA vaccines are under development |
| Treatment | Acyclovir, famciclovir and valacyclovir |
- How is HSV transmitted? → Horizontally by close contact and respiratory route (HSV-1) and genital tract (HSV-2); vertically through the placenta and birth canal
- Name the three types of HSV infection. → Primary, latent, recurrent
- Where do HSV-1 and HSV-2 lie latent? → Trigeminal ganglia and sacral ganglia
- How is HSV diagnosed and treated? → Cytopathology of scrapings, isolation, PCR, serology for IgM; treated with acyclovir, famciclovir or valacyclovir. No vaccine
Varicella zoster virus ★★★
| Detail | |
|---|---|
| Route of transmission | Respiratory route · contact with skin vesicles (blister fluid) |
| Primary infection | In children — CHICKENPOX (varicella) |
| Latent infection | Dorsal root ganglia or cranial sensory ganglia |
| Recurrence | In adults — HERPES ZOSTER |
The pathway
VZV enters by the respiratory route or contact → regional lymph node → primary viraemia → reticuloendothelial system → skin → VARICELLA (chickenpox), healing without scar → the virus becomes LATENT in the dorsal root ganglia or cranial sensory ganglia → on reactivation it travels back to the skin → ZOSTER.
| Disease | Features |
|---|---|
| 1 · Varicella (chickenpox) | The primary infection, usually in children. A mild, HIGHLY CONTAGIOUS disease. May be severe in adults and in immunocompromised children |
| 2 · Zoster (shingles) | Usually the recurrent form in adults. Characterised by a rash LIMITED IN DISTRIBUTION TO THE SKIN INNERVATED BY A SINGLE SENSORY GANGLION, with lesions similar to varicella and severe pain. The most common complication in elderly adults is POSTHERPETIC NEURALGIA |
| Detail | |
|---|---|
| Treatment | Acyclovir, valacyclovir, famciclovir |
| Prevention | A LIVE ATTENUATED varicella vaccine · a herpes zoster vaccine · varicella-zoster immunoglobulin, now available for post-exposure prophylaxis of high-risk patients who lack serologic evidence of immunity |
Chickenpox and shingles look nothing alike, and the difference is entirely in how the virus reaches the skin.
In varicella the virus arrives through the bloodstream — primary viraemia — so it seeds the skin everywhere at once. Hence a generalised rash, in crops, all over the body.
In zoster the virus arrives down a single sensory nerve from one reactivated ganglion. It can therefore only reach the skin that nerve supplies — so the rash is a band in one dermatome, stopping abruptly at the midline. That distribution is diagnostic on sight.
The severe pain and the postherpetic neuralgia follow from the same route: the virus is damaging a sensory nerve on its way out, which chickenpox never does.
And note the age pattern in the table — zoster is a disease of adults and the elderly, because reactivation happens as cell-mediated immunity to VZV wanes. That is why a zoster vaccine is given to older adults, separately from the childhood varicella vaccine.
- How is VZV transmitted? → By the respiratory route and contact with blister fluid
- Give the VZV pathway. → Entry → regional lymph node → primary viraemia → reticuloendothelial system → skin (varicella) → latency in dorsal root or cranial sensory ganglia → reactivation → skin (zoster)
- Describe varicella and zoster. → Varicella: primary infection in children, mild and highly contagious, severe in adults and the immunocompromised. Zoster: recurrence in adults, rash limited to the skin of a single sensory ganglion, with severe pain
- What is the commonest complication of zoster in the elderly? → Postherpetic neuralgia
- How is VZV prevented? → A live attenuated varicella vaccine, a herpes zoster vaccine, and varicella-zoster immunoglobulin for post-exposure prophylaxis in high-risk non-immune patients
Human cytomegalovirus ★★★
| Detail | |
|---|---|
| Source | Patients and persons with inapparent infection |
| Transmission | a. Close contact · b. blood transfusion and organ transplantation · c. sexual contact · d. vertical transmission |
| Histology | INTRANUCLEAR INCLUSION — seen on HE stain of, for example, lung |
⭐ Four clinical settings
| Setting | Features |
|---|---|
| 1 · Congenital infection — the virus infects the fetus through the placenta | Stillbirth, abortion, premature birth · CYTOMEGALIC INCLUSION DISEASE |
| 2 · Perinatal infection — through the birth canal or breast milk | Tends to be subclinical, with persistent viral shedding; favourable prognosis |
| 3 · Adolescents and adults | Usually asymptomatic; occasionally causes CMV MONONUCLEOSIS |
| 4 · Immunocompromised hosts | Pneumonia, RETINITIS, hepatitis |
Treatment: ganciclovir. A vaccine is being developed. The chapter summary adds: cytomegaloviruses are important causes of developmental defects and mental retardation after congenital infection, and inapparent infections with cytomegalovirus are common during childhood.
- How is CMV transmitted? → Close contact, blood transfusion and organ transplantation, sexual contact, and vertical transmission
- Name the four clinical settings. → Congenital (stillbirth, abortion, prematurity, cytomegalic inclusion disease) · perinatal (subclinical, shedding, good prognosis) · adolescents and adults (usually asymptomatic, occasionally CMV mononucleosis) · immunocompromised (pneumonia, retinitis, hepatitis)
- What is the characteristic histology? → Intranuclear inclusions
- How is CMV treated? → Ganciclovir
⭐ Epstein-Barr virus ★★★
“What diseases can be caused by EBV?” is question 9 on the TMU homework list — a brief answer in its own right.
EBV antigens — by the phase of the viral life cycle
| Phase | Antigen | Detail |
|---|---|---|
| Latent phase | EBV nuclear antigens (EBNA) | In the nucleus of B cells; DNA-binding proteins; function in stabilising the viral circular genome |
| Latent membrane proteins (LMP) | On the cell membrane of B cells; considered to be ONCOGENIC proteins | |
| Proliferative phase | Early antigen (EA) | Non-structural protein — DNA polymerase |
| Late antigens | Structural proteins — VCA and MA |
| Detail | |
|---|---|
| Transmission | Infected SALIVA (the main route) · sexual contact |
| Types of infection | Primary infection · latent infection and reactivation · MALIGNANT TRANSFORMATION |
| Primary infection | Children: usually subclinical. Young adults: acute infectious mononucleosis |
| Reactivation from latency | Causes latent infection of B cells in the presence of competent T cells. Once stimulated, viruses are reactivated — shown by increased virus in saliva and viral DNA in blood cells. In immunocompromised patients this may have serious consequences |
| Malignant transformation | EBV can INTEGRATE its viral gene into the chromosome of infected B cells to cause transformation or immortalisation. Continued B-cell proliferation together with other cofactors may result in lymphoma |
⭐ The diseases of EBV
| Disease | Features |
|---|---|
| 1 · Infectious mononucleosis | High fever, fatigue, sore throat, enlarged lymph nodes and spleen · an increase of ATYPICAL LYMPHOCYTES · HETEROPHILE ANTIBODY · the typical illness is SELF-LIMITED |
| 2 · Burkitt's lymphoma — found in equatorial Africa | The EBV genome can be demonstrated in the tumour cells · all patients have antibodies to EBV · EBV can transform human B lymphocytes in vitro |
| 3 · Nasopharyngeal carcinoma (NPC) — South-East Asian | The EBV genome can be detected in the malignant cells · 100% of sera from NPC patients have high-titre antibodies to EBV antigens · the antibody titre may decrease after treatment as the patient recovers |
| 4 · Lymphoproliferative disease | AIDS patients are susceptible to EBV-induced lymphoproliferative disease, such as ORAL HAIRY LEUKOPLAKIA · Hodgkin and non-Hodgkin lymphomas |
No drugs are available to treat EB virus. A vaccine is being developed.
EBV infects essentially everybody, and what happens next depends entirely on the T-cell response.
In children — subclinical. The immune system contains it silently.
In young adults — infectious mononucleosis. And here is the point students miss: the fever, sore throat, lymphadenopathy and splenomegaly are not the virus damaging tissue. The atypical lymphocytes in the blood film are activated cytotoxic T cells attacking EBV-infected B cells. The illness is the immune response — Unit 20 §5 again.
In the immunosuppressed — the brake comes off. The deck's phrase is precise: EBV causes latent infection of B cells in the presence of competent T cells. Remove those T cells and infected B cells proliferate unchecked: oral hairy leukoplakia and lymphoproliferative disease in AIDS and transplant patients.
With the right cofactors — malignancy. LMP is oncogenic, and the viral genome integrates and immortalises the B cell. Which cancer depends on geography: Burkitt's lymphoma in equatorial Africa (where holoendemic malaria is the cofactor) and nasopharyngeal carcinoma in South-East Asia.
One virus; four outcomes; the variable is the host.
- Name the EBV latent and proliferative antigens. → Latent: EBNA (nuclear, DNA-binding, stabilising the circular genome) and LMP (membrane, oncogenic). Proliferative: early antigen EA (DNA polymerase) and late antigens VCA and MA
- How is EBV transmitted? → Mainly by infected saliva; also by sexual contact
- Name the four EBV diseases. → Infectious mononucleosis · Burkitt's lymphoma · nasopharyngeal carcinoma · lymphoproliferative disease including oral hairy leukoplakia and Hodgkin and non-Hodgkin lymphoma
- Describe infectious mononucleosis. → High fever, fatigue, sore throat, enlarged lymph nodes and spleen, atypical lymphocytes, heterophile antibody; self-limited
- What links EBV to Burkitt's lymphoma and NPC? → The EBV genome is present in the tumour cells, all patients have EBV antibodies (100% high titre in NPC), and EBV transforms human B lymphocytes in vitro
- How does EBV transform cells? → It integrates its genes into the B-cell chromosome, causing transformation or immortalisation; continued proliferation with cofactors gives lymphoma
HHV-6, 7 and 8 ★★
| Virus | Detail |
|---|---|
| Human herpesvirus 6 (1986) | The causative agent of exanthem subitum (roseola infantum) |
| Human herpesvirus 7 | Related to HHV-6 |
| Human herpesvirus 8 | First detected in 1994 in Kaposi's sarcoma specimens. Also called Kaposi's sarcoma-associated herpesvirus (KSHV). Associated with the development of Kaposi's sarcoma in patients with AIDS — the chapter summary calls it the cause of Kaposi sarcoma, a vascular tumour |
- What does HHV-6 cause? → Exanthem subitum (roseola infantum)
- What is HHV-8? → Kaposi's sarcoma-associated herpesvirus (KSHV), the cause of Kaposi's sarcoma — a vascular tumour — in AIDS patients; first detected in 1994
⭐ The 2020 Section III answer
Then the members, each with its latency site and its diseases (6):
HSV-1 — latent in the trigeminal ganglia → gingivostomatitis, pharyngitis, herpes labialis (cold sores), keratoconjunctivitis, encephalitis.
HSV-2 — latent in the sacral ganglia → genital herpes, and neonatal herpes by vertical transmission.
VZV — latent in the dorsal root and cranial sensory ganglia → varicella (chickenpox) as the primary infection in children, and zoster (shingles) on reactivation in adults, with postherpetic neuralgia.
CMV → congenital cytomegalic inclusion disease with stillbirth, abortion and developmental defects; perinatal infection; CMV mononucleosis in adults; pneumonia, retinitis and hepatitis in the immunocompromised.
EBV — latent in B lymphocytes → infectious mononucleosis, Burkitt's lymphoma (equatorial Africa), nasopharyngeal carcinoma (South-East Asia), and lymphoproliferative disease including oral hairy leukoplakia in AIDS.
HHV-6 → exanthem subitum (roseola infantum).
HHV-8 (KSHV) → Kaposi's sarcoma in AIDS patients.
Naming the latency site for each is what separates a good answer from a list. If space allows, close with the treatment: acyclovir and its relatives for HSV and VZV, ganciclovir for CMV, and no drug for EBV.
Revision
⭐ The family on one screen
| Virus | Latency site | Diseases | Treatment |
|---|---|---|---|
| HSV-1 | Trigeminal ganglia | Gingivostomatitis, pharyngitis, cold sores, keratoconjunctivitis, encephalitis | Acyclovir, famciclovir, valacyclovir |
| HSV-2 | Sacral ganglia | Genital herpes, neonatal herpes | As above |
| VZV | Dorsal root / cranial sensory ganglia | Varicella (children) → zoster (adults), postherpetic neuralgia | Acyclovir; live attenuated and zoster vaccines |
| CMV | Leukocytes | Cytomegalic inclusion disease, CMV mononucleosis, pneumonia, retinitis, hepatitis | Ganciclovir |
| EBV | B lymphocytes | Infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma, lymphoproliferative disease | No drug available |
| HHV-6 | — | Exanthem subitum (roseola infantum) | — |
| HHV-8 (KSHV) | — | Kaposi's sarcoma in AIDS | — |
- Answer the 2020 question. → Large enveloped dsDNA viruses, all establishing lifelong latency; HSV-1 (trigeminal, cold sores), HSV-2 (sacral, genital herpes), VZV (dorsal root, chickenpox then zoster), CMV (congenital disease, retinitis in AIDS), EBV (mononucleosis, Burkitt's, NPC), HHV-6 (roseola), HHV-8 (Kaposi's sarcoma)
- Name the diseases caused by EBV. → Infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma, lymphoproliferative disease including oral hairy leukoplakia and Hodgkin and non-Hodgkin lymphoma
- Why do herpesviruses reactivate in the immunocompromised? → All establish lifelong latency held in check by T cells; losing T-cell function releases them
- Why is zoster a dermatomal rash while varicella is generalised? → Varicella reaches the skin by viraemia, everywhere at once; zoster travels down one sensory nerve from a single reactivated ganglion
- Which two EBV antigens are oncogenic or nuclear? → LMP is considered oncogenic; EBNA are nuclear DNA-binding proteins stabilising the circular genome