Identification of new herpesvirus gene homologs in the human genome

Abstract

Viruses are intracellular parasites that use many cellular pathways during their replication. Large DNA viruses, such as herpesviruses, have captured a repertoire of cellular genes to block or mimic host immune responses, apoptosis regulation, and cell-cycle control mechanisms. We have conducted a systematic search for all homologs of herpesvirus proteins in the human genome using position-specific scoring matrices representing herpesvirus protein sequence domains, and pair-wise sequence comparisons. The analysis shows that approximately 13% of the herpesvirus proteins have clear sequence similarity to products of the human genome. Different human herpesviruses vary in their numbers of human homologs, indicating distinct rates of gene acquisition in different lineages. Our analysis has identified new families of herpesvirus/human homologs from viruses including human herpesvirus 5 (human cytomegalovirus; HCMV) and human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus; KSHV), which may play important roles in host-virus interactions.

Figure 1

Alignment of new herpesvirus/human homologs. Proteins are labeled with GenBank identification number (GI) and a short description. Amino acids that are shaded red share identity across ≥50% of the alignment; amino acids shaded grey share similarity across ≥50% of the alignment. (a) Herpesvirus US12 protein family members, human lifeguard protein, and two additional human proteins. The Pfam UPF0005 domain is indicated. (b) HCMV UL1, two PSG proteins (PSβG 5 and 13), and one member of the carcinoembryonic antigen subfamily (NCA, nonreacting antigen). (c) A representative from each of the herpesvirus protein families found to contain C-type lectin domains and two natural killer receptors (NKG2-A). The four conserved cysteines, important for disulphide bond formation in the carbohydrate recognition domain, are indicated. (d) K3/K5 herpesvirus protein family with six human homologs. Cysteine/histidine conserved residues in the BKS (BHV-4 [bovine herpesvirus 4], KSHV, and swinepox) motif are indicated.

Figure 2

Human herpesvirus (HHV) proteins with human homologs. Alternative names for the HHVs are HHV-1, human simplex virus 1; HHV-2, human simplex virus 2; HHV-3, varicella zoster virus; HHV-4, Epstein-Barr virus; HHV-5, human cytomegalovirus; and HHV-8, Kaposi's sarcoma–associated herpesvirus. Labels show the virus protein function, the name of a member of the HPF (homologous protein family) or singleton, and, for HPFs, the corresponding number in brackets. All the annotations and HPF numbers are taken from VIDA. Note that in some cases more than one HPF/singleton, shown as separate rows in Table 1, are shown together here. This corresponds to highly divergent families. The graph is color coded according to functional class: light green, DNA replication; dark blue, nucleotide repair/metabolism; light blue, enzyme; purple, gene expression regulation; yellow, glycoprotein; red, host-virus interaction; and black, unknown. Diagonal lines within a box indicate two gene copies (per viral genome); vertical lines, three copies; and horizontal lines, 10 copies.

Figure 3

Gammaherpesvirus-specific proteins involved in host-virus interactions that have human homologs. Boxes indicate the presence of a particular gene(s) in a virus genome. Numbers in boxes represent copies within a genome. Labels show the virus protein function, the name of a member of the HPF (homologous protein family) or singleton, and, for HPFs, the corresponding number in brackets. All the annotations and HPF numbers are taken from VIDA. Note that in some cases more than one HPF/singleton, shown as separate rows in Table 1, is shown together. This corresponds to highly divergent families. The HPF/singletons that are not present in Table 1 are represented as unfilled boxes. These are herpesvirus proteins for which we did not identify human homologs in the database searches but that, nevertheless, can be grouped together, by function and residue conservation, with other herpesvirus HPF/singletons for which we could detect human homologs. A consensus phylogenetic tree of the gammaherpesvirus is shown at the bottom. This was generated as described for all HPFs from complete herpesvirus genomes (Albà et al. 2001a).