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Definition
Herpesvirus has an outer envelope surrounding a capsid and the genomic DNA is a linear double strand, arranged as a toroid wound round a protein plug. Glycoprotein B (gB) is the most conserved glycoprotein of herpesviruses and plays important roles in virus infectivity. Bovine herpesvirus encodes proteins that inhibit specific arms of the immune system. Many synthetic peptides derived from these proteins have shown the ability to inhibit virus replication.

Discovery
Several herpesviruses have been found to induce novel ribonucleotide reductase activities. The herpesviruses enzyme consists of two summits: V136, the large subunit of relative molecular mass (M r) 136,000 (136K) (RR1) and V38, the small subunit (RR2) which forms a complex with the large subunit and is also likely to be essential for enzyme activity. Dutia  BM et al., in 1986 identifed a synthetic peptide which specifically inhibits the activity of virus-induced enzyme. They deduced the mechanism of inhibition involves interference with the normal interaction between the two types of subunit 1,2. Okazaki K et al., in 2004 identified amphipathic heptad repeat (HR) regions within gBs of different herpesviruses and demonstrate that a synthetic peptide derived from one of the regions within BoHV-1 gBc bound to the glycoprotein and inhibited the replication of BoHV-1. The peptide did not affect virus entry but interfered with cell-to-cell spread to reduce virus production 3.

Structural Characteristics
Two HR regions were detected in the amino acid sequences of gB of all the herpesviruses analysed. Bovine herpesvirus type 1 (BoHV-1)gB HR1 region commenced 39 aa from the cleavage site and the HR2 region was 22 aa away from the transmembrane (TM) domain. Hydrophobic (I, L, M and V) and aromatic (F, Y and W) amino acids were predominant at the heptad positions of ‘a’ and ‘d’ where the sequences were highly conserved. Helical-wheel representations of the HR1 and HR2 of BoHV-1 gB illustrate the amphipathic property of the regions. In particular, the HR1 region represented a leucine zipper motif 3.  Kaposi's Sarcoma-Associated Herpes Virus (KSHV) Protease Substrates, Ac-Val-Tyr-Leu-Lys-Ala-SBzl is used for development of a high throughput colorimetric assay for inhibitor screening 4. HSV-1 Proteinase Substrates,H-His-Thr-Tyr-Leu-Gln-Ala-Ser-Glu-Lys-Phe-Lys-Met-Trp-Gly-NH2 is highly characterized substrate for herpes simplex virus type 1 protease (HSV-1), which is essential for viral nucleocapsid formation and for viral replication 5.

Mode of Action
The ability of bovine herpesvirus type 1 (BHV-1) to impair the immune response can lead to bovine respiratory disease complex (BRDC). Two viral genes, the latency related gene and ORF-E are abundantly expressed during latency, regulate the latency-reactivation cycle. The ability of BHV-1 to enter permissive cells, infect sensory neurons and promote virus spread from sensory neurons to mucosal surfaces following reactivation from latency is also regulated by several viral glycoproteins 6. Infection of cattle with bovine herpesvirus-1 (BHV-1) impairs the cell-mediated immune response (CMI) of the affected host. Interference of BHV-1 with the major histocompatibility complex (MHC) class I antigen presentation pathway was investigated. A considerable down-regulation of the peptide transport activity in bovine epithelial cells, taking place as early as 2 h after virus infection. This down-regulation was also dose-dependent, and, at high multiplicities of infection (moi), led to an almost complete shutdown of TAP. By inhibiting peptide transport into the ER, the virus impairs loading of MHC class I molecules and their subsequent egress from the ER to the cell surface. Thus, BHV-1 selectively interferes with the host's antigen presentation machinery to evade the host's immune response in vivo 7

Functions

Inhibition of immune system, BHV-1 encodes at least three proteins that can inhibit specific arms of the immune system: (i) bICP0 inhibits interferon-dependent transcription, (ii) the UL41.5 protein inhibits CD8+ T-cell recognition of infected cells by preventing trafficking of viral peptides to the surface of the cells and (iii) glycoprotein G is a chemokine-binding protein that prevents homing of lymphocytes to sights of infection. Following acute infection of calves, BHV-1 can also infect and induce high levels of apoptosis of CD4+ T-cells 6.

Inhibit virus replication, a synthetic peptide derived from the HR region (aa 477–510) of bovine herpesvirus type 1 (BoHV-1) Glycoprotein B (gB) interfered with cell-to-cell spread and consistently inhibited replication of BoHV-1 3.

Antiviral drug, several interactions between virus proteins have been proposed as attractive targets for antiviral drug discovery of herpesvirus, as the exquisite specificity of such cognate interactions affords the possibility of interfering with them in a highly specific and effective manner. Most drugs active against herpesviruses, target the polymerisation activity of the virus DNA polymerase, are limited by pharmacokinetic issues, toxicity and antiviral resistance. A potential novel target for anti-herpesvirus drugs is the interaction between the two subunits of the virus DNA polymerase. 8.

References

  1. Dutia BM, Frame MC, Subak-Sharpe JH, Clark WN, Marsden HS (1986). Specific inhibition of herpesvirus ribonucleotide reductase by synthetic peptides. Nature., 321:439-441.
  2. Frame MC, Marsden HS, Dutia BM (1985). The ribonucleotide reductase induced by herpes simplex virus type 1 involves minimally a complex of two polypeptides (136K and 38K). J Gen Virol., 66:581-587.
  3. Okazaki K, Kida H (2004). A synthetic peptide from a heptad repeat region of herpesvirus glycoprotein B inhibits virus replication. J Gen Virol., 85:2131-2137.
  4. Pray TR, Nomura AM, Pennington MW, Craik CS (1999). Auto-inactivation by cleavage within the dimer interface of Kaposi's sarcoma-associated herpesvirus protease. J. Mol. Biol., 289(2):197-203.
  5. Hall DL, Darke PL (1995). Activation of the herpes simplex virus type 1 protease. J. Biol. Chem., 270(39):22697-22700.
  6. Jonesa C,Chowdhurya S (2007). A review of the biology of bovine herpesvirus type 1 (BHV-1), its role as a cofactor in the bovine respiratory disease complex and development of improved vaccines. Animal Health Research Reviews, 8:187-205.
  7. Hinkley S, Hill AB, Srikumaran S (1998). Bovine herpesvirus-1 infection affects the peptide transport activity in bovine cells. Virus Research., 53(1):91-96.
  8. Loregian A, Palù G (2005). Disruption of the interactions between the subunits of herpesvirus DNA polymerases as a novel antiviral strategy. Clinical Microbiology and Infection, 11(6):437-446.

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