Gammaherpesvirinae

VIRION

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Enveloped, spherical to pleomorphic, 150-200 nm in diameter,T=16 icosahedral symmetry. Capsid consists of 162 capsomers and is surrounded by an amorphous tegument. Glycoproteins complexes are embeded in the lipid envelope.

GENOME

Monopartite, linear, dsDNA genome of about 180 kb. The genome contains terminal and internal reiterated sequences.

GENE EXPRESSION

Each viral transcript usually encodes a single protein and has a promoter/regulatory sequence, a TATA box, a transcription initiation site, a 5' leader sequence of 30-300 bp (not translated), a 3' nontranslated sequence of 10-30 bp, and a poly A signal. There are many gene overlaps. There are only few spliced genes. Some of the expressed ORFs are antisense to each other. Some ORFs can be accessed from more than one promoter. There are some non-coding genes.

REPLICATION

NUCLEAR

Lytic replication:

  1. Attachment of the viral glycoproteins to host receptors mediates endocytosis of the virus into the host cell.
  2. Fusion with the plasma membrane to release the core and the tegument proteins into the host cytoplasm.
  3. The capsid is transported to the nuclear pore where the viral DNA is released into the nucleus.
  4. Transcription of immediate early genes which promote transcription of early genes and protect the virus against innate host immunity.
  5. Transcription of early viral mRNA by host polymerase II, encoding proteins involved in replication of the viral DNA.
  6. A first round of circular genome amplification occurs by bidirectional replication
  7. Synthesis of linear concatemer copies of viral DNA by rolling circle.
  8. Transcription of late mRNAs by host polymerase II, encoding structural proteins.
  9. Assembly of the virus in nuclear viral factories and budding through the inner lamella of the nuclear membrane which has been modified by the insertion of herpes glycoproteins, throughout the Golgi and final release at the plasma membrane.

Latent replication : replication of circular viral episome in tandem with the host cell DNA using the host cell replication machinery.

Host-virus interaction

Adaptive immune response inhibition

Gamma-herpesviruses have evolved different strategies to inhibit the host adaptive immune response. For example, the EHV-2 viral interleukin-10 homolog down-regulates the expression of the TAP1 gene (transporter associated with antigen processing), thereby affecting the transport of peptides into the endoplasmic reticulum and subsequent peptide loading by MHC class I molecules.

Apoptosis modulation

Apoptosis is very often modulated (and usually inhibited) by gamma-herpesviruses. For example, Epstein-Barr, HHV-8 or AlHV-1 all possess a viral homologue of the Bcl-2 oncogene that is able to protect cells from induced apoptosis.

Autophagy modulation

Several gamma-herpesviruses are able to inhibit host autophagy process, via interaction of vBcl-2 and vFLIP with host Beclin 1 and Atg3 respectively, that impact two stages of autophagy.

Cell-cycle modulation

The UL24 protein that is present in all herpesvirus subfamilies (alpha, beta and gamma-herpesviruses) induces a cell cycle arrest at G2/M transition through inactivation of the host cyclinB/cdc2 complex .

Innate immune response inhibition

Herpes viruses inhibit the cascade leading to production of interferon-beta by mainly targeting the host IRF3 protein. EBV inhibits the cascade leading to production of interferon-beta by targeting host IRF3 protein with the BGLF4 protein kinase that directly interacts with and inhibits host IRF3. BRLF1 expression also decreases induction of IFN-beta, and reduces expression of IRF3 and IRF7.

Host splicing inhibition

Modulates the host mRNA expression by exporting unspliced mRNA, thereby inducing alternative splicing .