HHV6

Question 1

SubFamilies of herpes viruses

Answer 1

1. Alphaherpesvirinae: HSV1, HSV2, VZV - neurotrophic
2. Betaherpesvirinae: CMV, HHV6, HHV7 - less confined tropism.
3. Gammaherpesvirinae: EBV, HHV8 - lymphotropic

Question 2

HHV 6 structure

Answer 2

Linear dsDNA, 200nm size

3 main structural elements shared by all herpes viruses:

1. Nucleocapsid - icosahedral contains viral DNA genome
2. Envelope with embedded viral glycoproteins
3. Tegument - protein mixture occupying space between nucleocapsid and envelope

Baltimore - I

Question 3

Strains of HHV6

Answer 3

HHV6-A & HHV6-B

HHV6-A: Benign
HHV6-B: exanthema subitum & encephalitis.

90% nucleotide sequence identity between strains.

Question 4

HHV6 entry & replication

Answer 4

Receptor - CD46 (glycoprotein) present on membrane of all nucleated cells and is physiologically involved in complement regulation.

Replicates in CD4 T lymphocytes, fibroblasts, monocytes, macrophages, NK cells, endothelial and epithelial cells.

Establishes latency after primary infection. Persistent infection in salivary glands and brain tissue but latent in monocytes and early BM progenitor cells.

Reactivates during superinfection with HHV7.

Question 5

Chromosomally integrated HHV6

Answer 5

Universal postnatal acquisition of HHV6-B in humans.

1% people, HHV6A or B integrates into chromosomal telomere in every uncleared cell in the body and is transmitted through Mendelian inheritance.

In CIHHV6, high VL seen in both whole blood while in infection, replication leads to VL in ‘cell free samples’.

CIHHV6 can potentially reactivate in post HSCT and profound immunosuppression.

Question 6

HHV 6 clinical syndromes

Answer 6

1. Primary infection - erythema subitum & roseola Infantium
2. Reactivation
3. Reinfection
4. CIHHV6
5. Donor derived CIHHV6

Question 7

Diagnosing CIHHV6

Answer 7

Persistently high VL in whole blood (>5.5 logs) and 100-fold lower levels in serum.

Digital PCR - one copy of HHV6 per cellular genome confirm CIHHV6.

FISH - demonstrates HHV6 integrated into human chromosome.

Question 8

HHV6-B post HSCT

Answer 8

1. Primary - 2 cases described
2. Reactivation - rash and encephalitis.
3. CIHHV6-B can reactivate and cause encephalitis in theory.

HHV6-B end organ disease: Fever and rash, limbic encephalitis, myelitis, Murli suppression and graft failure, hepatitis, pneumonitis, GVHD

HHV6-B encephalitis:

1. Compatible clinical syndrome
2. DNA detected in CSF
3. Exclude other causes
4. Exclude CIHHV6 in both donor and recipient
5. Plasma HHV6 DNAemia supportive

25% mortality

For HHV6 end organ damage - test tissue for culture/IHC/FISH/Rt-PCR for mRNA rather than DNA.

Question 9

HHV6 treatment

Answer 9

Ganciclovir, Foscarnet, cidofivir - invitro activity
Brincidofovir - in vitro activity
Virus specific T cells being studied

Encephalitis:

1st line - Foscarnet 90mg/Kg BD or Ganciclovir 5mg/kg BD for 3 weeks and negative blood/CSF

Combination therapy can be considered

Question 10

Differentiating between HHV-6 & CIHHV6

Answer 10

1. CIHHV6 will have high VLs: >10x6 copies in peripheral whole blood with 2 logs less in plasma.
2. FISH with a specific HHV-6 probe performed on metaphase chromosome preparations from peripheral blood will demonstrate integrated HHV-6.
3. CIHHV6 - detectable HHV-6 in their hair follicles, PCR testing of hair follicles for HHV-6 DNA can be performed.
4. Droplet digital PCR - 1viral copy/1 cell implies integrated virus.