Department of Animal and Food Sciences, University of Delaware, Newark, DE 19717, USA1
Institute of Virology, Slovak Academy of Sciences, Dúbravská cesta 9, 842 45 Bratislava, Slovak Republic2
Author for correspondence: Carl Schmidt. Fax +1 302 831 8177. e-mail schmidtc{at}udel.edu
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Abstract |
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Introduction |
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HVT and MDV are both avian alphaherpesviruses. Their genomes consist of two distinct regions, L and S, that are composed of unique long (UL) and unique short (US) sequences bounded by inverted repeats. The genomic organization of UL has been remarkably conserved during the evolution of these herpesviruses. The US region, while containing obvious homologues conserved in the different alphaherpesviruses, is more variable in both its organization and gene content.
We have completed the DNA sequence of the UL region, the long internal repeat (IRL) and the inverted repeats of the short region (complete IRS and partial TRS) of HVT. As sequences of the complete MDV-1 genome and the UL and US regions of MDV-2 are available (Brunovskis & Velicer, 1995 ; McKie et al., 1995
; Jang et al., 1998
; Lee et al., 2000
; Tulman et al., 2000
), our data provide a tool for comparative analysis of all three serologically related avian herpesviruses. The gene organization within the HVT UL and US regions is clearly conserved relative to other alphaherpesviruses. In addition, HVT encodes seven genes that are found in both MDV-1 and HVT (MDV-2 shares six of them), but are absent from the sequenced genomes of other alphaherpesviruses. Among these genes is one encoding a product with similarity to cellular phospholipases. Another gene, present in HVT but absent from MDV-1, encodes a product that is similar to the quail anti-apoptotic protein NR-13. A striking feature is the different genetic organization within the repeat regions.
Partial sequences of the HVT genome have been reported previously (Kato et al., 1989 ; Martin et al., 1989
; Scott et al., 1989
, 1993
; Coussens et al., 1990
; Zelník et al., 1993
; Smith et al., 1995
; Kopá
ek et al., 1997
). However, these sequences represent only a small portion of the HVT genome. The data presented in this paper compile the complete encoding potential of HVT, enabling subsequent expression and functional analysis of its genetic elements.
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Methods |
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Bioinformatics.
DNA sequences were aligned by using the GCG software package. Further analysis was performed with the programs OPEN READING FRAME, BLAST and PSI-BLAST (Altschul et al., 1997 ). Additional analysis was conducted with the web-based programs GRAIL (Uberbacher & Mural, 1991
), MOTIF (Bucher & Bairoch, 1994
), PSORT, ProDom and DIALIGN 2 (Morgenstern et al., 1996
).
Source of sequences.
The accession numbers of the sequences included in the analysis were as follows: MDV-1, AF147806; MDV-2, AB049735; herpes simplex virus type 1 (HSV-1; human herpesvirus-1), NC 001806; varicella-zoster virus (VZV), NC 001348; bovine herpesvirus-1 (BHV-1), NC 001847; equine herpesvirus-1 (EqHV-1) UL45, P36323; quail NR-13 homologue, Q90343; chicken Bcl-x, A47537; pseudorabies virus (PRV) gC, AAF28243; EqHV-1 UL54 homologue, Q05906.
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Results and Discussion |
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In herpesviruses that infect mammals, gC plays an important role in binding heparan sulphate, an initial step in virus infection (Shieh et al., 1992 ; Spear et al., 1992
; WuDunn & Spear, 1989
). In addition, gC binds and inhibits complement C3b, which may be important for immune evasion (Lubinski et al., 1998
). The infectious laryngotracheitis virus (ILTV) gC protein lacks a heparan sulphate-binding domain, and heparan sulphate does not appear to play a role in the initial stages of infection by ILTV (Kingsley & Keeler, 1999
). Comparison of HVT gC with those of PRV and HSV-1, which have mapped heparan sulphate-binding domains, suggests that HVT may also lack a heparan-binding domain (Fig. 2a
).
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Additional predicted membrane-associated proteins
Homologues of HSV-1 genes UL20, UL34, UL43 and UL45 are found in HVT. Based upon sequence similarity, it is predicted that the HVT genes UL20, UL34 and UL43 are orthologues of the respective genes found in HSV-1 (McGeoch et al., 1988 ; Baines et al., 1991
). In contrast to these predicted membrane proteins, the HVT gene UL45 shows little similarity to HSV-1 UL45 (Table 2
) but strong similarity to MDV UL45 (Lee et al., 2000
; Izumiya et al., 1998
) and EqHV-1 gene 15 (Telford et al., 1992
) (not shown).
Regulatory proteins
The HVT genome is predicted to encode two protein kinases, UL13 and US3; both gene products contain motifs associated with kinase activity of other homologous proteins (Ng et al., 1994 ; Purves & Roizman, 1992
; Purves et al., 1992
).
The HVT UL41 gene product is similar to other herpesvirus proteins that are responsible for inhibition of host protein synthesis (Kwong & Frenkel, 1989 ). Inhibition appears to occur by UL41 promoting the degradation of host mRNA (Pak et al., 1995
). PSI-BLAST analysis revealed weak similarity of the HVT UL41 gene product to the RAD13 and FEN-1 endonucleases (not shown). However, it is not certain whether UL41 homologues function directly as nucleases or modulate a cellular ribonuclease (Elgadi et al., 1999
; Zelus et al., 1996
).
When compared with HSV-1, HVT lacks the ICP0 gene, which plays a role in modulating HSV-1 mRNA levels. In contrast, the MDV-1 RLORF1 gene product displays weak similarity to HSV-2 ICP0 (Lee et al., 2000 ). The HVT US1 gene is much smaller than those homologues found in other herpesviruses. Three of the major gene-regulatory proteins identified in HSV-1, VP16 (UL48), ICP27 (UL54) and ICP4, are encoded in the HVT genome. The HSV-1 proteins encoded by the genes UL46, UL47 and UL49 all interact with VP16 (Elliott et al., 1995
; Zhang et al., 1991
). HSV-1 VP16 is responsible for induction of the early genes of the virus (Campbell et al., 1984
; Dalrymple et al., 1985
) and the HSV-1 UL46 and UL47 gene products are believed to modulate VP16 activity (Zhang et al., 1991
). The significant difference between HVT VP16 and HSV-1 VP16 is the absence of a carboxy-terminal acid-rich region that functions in gene activation. This region is also absent from the MDV-1 VP16 homologue (Yanagida et al., 1993
). The domain of HSV-1 VP16 involved in interaction with the HSV-1 UL49 gene product (VP22) has been mapped to this acid-rich region (Elliott et al., 1995
), suggesting that HVT VP16 and HVT VP22 may not interact. However, it should be noted that HVT VP16 displays more similarity to ORF10 of VZV, which contains an activation domain at the amino terminus of the protein (Kopá<
ek et al., 1997
).
HSV-1 ICP27 controls gene expression at the level of mRNA processing (Sandri-Goldin, 1998 ). HVT ICP27 contains multiple nuclear-localization signals consistent with the nuclear role of other herpesvirus UL54 products (not shown). Furthermore, the carboxy-terminal zinc finger domain (CCCH class) of HSV-1 ICP27 has been implicated in its regulatory functions (Zhi et al., 1999
), and this domain is also conserved in HVT ICP27 (Fig. 3a
). These characteristics suggest that HVT ICP27 plays a role in nuclear post-transcriptional gene regulation.
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Novel ORFs
In addition to the conserved genes shared by other alphaherpesviruses, HVT contains at least nine ORFs that are not common to all herpesviruses. Homologues of seven of these genes are readily identified in MDV-1 and MDV-2. One of the genes described below, specific for HVT and encoded by RSORF1 (ORF 65), is a homologue of a cellular gene that regulates apoptosis.
HVT LORF1.
The product of this ORF appears to be encoded by a spliced transcript, with a homologous gene at a similar position in MDV. The homologous MDV-1 gene is transcribed and undergoes splicing to yield a single processed transcript (Becker et al., 1994 ). Database analysis did not reveal homologues in any herpesviruses other than MDV-1 and MDV-2 (LORF2 and ORF759, respectively). However, these protein sequences show similarity to gene products found in some avian adenoviruses, including fowl adenovirus type 8 (Fig. 4
). The HVT product of the spliced LORF1 mRNA shows similarity to proteins involved in lipid metabolism and transport, including triacylglycerol lipase, phospholipase A1, lipoprotein lipase and insect yolk proteins. The active site of lipases contains a catalytic triad of amino acids responsible for hydrolysis of lipids (Dodson et al., 1992
). Inspection of the HVT LORF1 alignment revealed that only one of the three residues, corresponding to the HVT LORF1 serine residue at position 198, is conserved between lipases and the HVT gene product. In addition, similarly to lipid-associating proteins, the HVT-encoded protein contains one predicted trans-membrane domain, between amino acids 21 and 35. This combined analysis leads us to speculate that HVT LORF1 may encode a membrane protein that either binds or metabolizes lipids.
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HVT LORF4.
Homologues of this gene are found in MDV-1 (MDV LORF10), BHV-1 (circ protein, IE R1.5), EqHV-1 (KyA strain ORF1) and VZV (ORF2), but not in HSV-1 or MDV-2. MOTIF analysis predicted that HVT LORF4 encodes an amino-terminally myristoylated protein. Myristoylation would be predicted to localize the encoded protein to either intracellular membranes or the plasma membrane (McCabe & Berthiaume, 1999 ). This potential amino-terminal myristoylation site is conserved in BHV-1 and EqHV-1 but absent from VZV.
HVT LORF3, LORF5 and LORF6.
The only clear homologues to these putative ORFs are found in MDV-1 and MDV-2 (Table 2). MOTIF analysis yielded no similar motifs or domains currently deposited in the public databases. The coding region of HVT LORF5 exhibits 47% identity to HVT LORF3, suggesting a specific duplication of this gene in HVT during the evolution of these herpesviruses.
HVT RSORF1 (NR-13 homologue).
The product of this ORF is encoded by a spliced mRNA and displays significant similarity to the quail anti-apoptotic gene NR-13 (Fig. 5) (Gillet et al., 1995
; Mangeney et al., 1996
). The MDV-1 genome does not contain a relative of this gene. BLAST and MOTIF analysis showed clear similarity of the encoded product to other proteins that regulate apoptosis, including Bcl-2 and Bcl-x (reviewed by Chinnaiyan, 1999
). The BH1 and BH2 domains can both be identified in the encoded HVT NR-13 protein sequence. These two domains are essential for the anti-apoptotic properties of members of the Bcl family (Reed, 1996
). In addition, a region of partial similarity to the BH3 domain of apoptosis-regulating proteins is also found. In contrast to BH1 and BH2, the BH3 domain typically promotes apoptosis (Inohara et al., 1997
). Finally, the carboxy terminus of the HVT NR-13 protein is predicted to contain a membrane-association domain. This is consistent with the membrane attachment of other Bcl-like proteins (Chen-Levy et al., 1989
; Hockenbery et al., 1990
; Gillet et al., 1995
). These observations suggest that the HVT NR-13 gene encodes a membrane-associated protein that might regulate apoptosis. The presence of this gene product may explain the ability of HVT, but not MDV-1 strains, to inhibit apoptosis in the DT40 B cell line (Ewert & Duhadaway, 1999
).
|
In addition to the truncation of pp38, HVT lacks several genes identified in the repeat regions of MDV. Of potential importance is the absence of genes implicated in oncogenesis. The meq gene, which belongs to the fos/jun class of transcriptional activators and may play a key role in MDV-induced T-cell lymphomas (Jones et al., 1992 ; Liu et al., 1998
; Xie et al., 1996
), is clearly absent from HVT. In addition, at least nine other ORFs identified in MDV GA strain (Lee et al., 2000
) are also absent from HVT. These include the vIL-8 homologue, which has been speculated to recruit cells for infection or to diminish IL-8-mediated responses (Lee et al., 2000
). However, other genes identified within RL and RS may also be important for MDV-1 oncogenesis.
Evolution of HVT
Individual genes from the HVT UL region and other herpesviruses were compared by using CLUSTAL W (Higgins & Sharp, 1988 ) to align the protein products and to generate trees. The genes analysed included the small (UL40) and large (UL39) subunits of ribonucleotide reductase, exonuclease (UL12), thymidine kinase (UL23), dUTPase (UL50), DNA polymerase (UL30), UL8, UL42 and UL5. Fig. 6
shows one such tree generated by using the DNA polymerase genes. The results for DNA polymerase were typical of those obtained for other HVT genes. In this analysis, we included the mouse DNA polymerase
as an outgroup. The alpha-, beta- and gammaherpesvirus DNA polymerase genes each formed individual phyletic groups. An initial branching event led to the alpha- and beta- plus gammaherpesvirus families, with subsequent divergence of the beta- and gammaherpesviruses. Within the alphaherpesviruses, ILTV appears to have arisen earliest. Subsequently, a branch leading to HVT and MDV-1 and -2 splits off, followed by clustering of the remaining mammalian herpesvirus DNA polymerases. The combined results support the evolution of HVT and MDV early in the alphaherpesvirus radiation, as has been noted in other analyses of herpesvirus evolution (Karlin et al., 1994
; McGeoch & Cook, 1994
; McGeoch et al., 1995
; McGeoch & Davison, 1999
).
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Acknowledgments |
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Footnotes |
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Received 9 October 2000;
accepted 7 December 2000.