Role of ICP0 in the Strategy of Conquest of the Host Cell by Herpes Simplex Virus 1

In early studies, herpes simplex virus 1 (HSV-1) proteins were identified on the basis of two criteria. The first consisted of characterization of proteins contained in virions purified from cells whose proteins were labeled prior to infection. These proteins designated by the prefix VP were numbered in the order of decreasing apparent molecular weight or, conversely, ascending electrophoretic mobility in denaturing gels (147). The second criterion identified putative viral proteins accumulating in infected cells but absent from uninfected cells. These proteins, designated infected-cell proteins (ICPs), were also numbered in order of decreasing apparent molecular weight (73). One protein, however, while clearly apparent only in infected cells, varied with respect to electrophoretic mobility depending on the composition of the denaturing gel (74). This anomalously migrating protein was designated ICP0 (74). In subsequent studies, viral proteins were designated either by their known primary function (e.g., DNA polymerase, etc.) or the position of the gene along the unique long (UL) or short (US) components of the viral genome (105, 107). The original ICP designation, however, was retained primarily for five proteins recognized in early studies as being the products of α or immediate-early genes expressed after infection in the absence of de novo viral protein synthesis (74, 75). The five proteins, ICP0, ICP4, ICP22, ICP27, and ICP47, have been extensively studied, and for the most part, there is at least a semblance of concordance between the phenotype of cells infected with the mutant lacking the gene, the behavior of the protein in transduced cells, and the molecular functions expressed by the protein (reviewed in reference 132). ICP4 is an essential positive and negative regulator of gene expression (reviewed in reference 132). The protein blocks gene expression by binding to high-affinity DNA consensus sites located at transcription initiation sites of at least two genes. The mechanism of gene activation is less understood, although ICP4’s affinity for transcription factors and binding to highly degenerate or nonconsensus sites are suggestive of how it might act. ICP27 is also a multifunctional protein whose phenotype can be largely explained by its ability to block RNA splicing but not transport of unspliced RNA early in infection and by its activity as a chaperone of newly made viral mRNA across the nuclear membranes at late times after infection (reviewed in reference 137). Available data indicate that the carboxyl-terminal half of ICP22 enables full expression of a subset of late (γ2) viral genes by causing cdc2 cyclin-dependent kinase activity to survive the degradation of its physiologic partners cyclins A and B, by an aberrant partnership with the UL42 DNA polymerase processivity factor (2, 5, 6, 19, 141). Optimal transcription of late genes requires binding and posttranslational modification of topoisomerase IIα by the two proteins (7). The sole known mission of ICP47 is to bind to and preclude TAP1/TAP2 from enabling the transport of antigenic peptides into the endoplasmic reticulum for eventual presentation on the cell surface (50, 71, 161). Despite 3 decades of research and enormous interest, it is not known how the functions encoded in ICP0 account for its phenotype in either infected or transduced cells. However, available evidence suggests that ICP0 is a multifunctional protein and that its role in viral infection reflects the sum of its multiple and diverse functions (132). Studies published nearly 20 years ago established that ICP0 activates genes introduced into cells by transfection or infection (29, 30, 54, 118, 129). Furthermore, ICP0 also activates a specific subset of cellular genes, including several p53-responsive genes that it activates independently of p53 (72). ICP0 is considered a promiscuous transactivator, inasmuch as it activates transcription from HSV (16, 22, 104) and heterologous (58, 114, 143) promoter elements independently of a single cis-acting element (40). ICP0 activates transcription of viral genes in synergy with or independent of ICP4 (29, 31, 55, 129). ICP0 has been shown to interact with ICP4, and this interaction is believed to mediate cooperative activation of gene expression, as it maps to a region of ICP0 (residues 617 to 775) that contains the domain involved in synergy with ICP4 (residues 680 to 767) (33, 159). In most cell lines infected at low multiplicity with mutants lacking the gene encoding ICP0 (Δα0), viral yields are 10- to 100-fold lower than those from cells infected with wild-type virus (34, 136, 148). At higher multiplicities of infection, viral yields and protein expression are similar to those of wild-type virus (34, 136, 148). Exceptions are a few cell lines, exemplified by the line U20S, in which Δα0 mutants replicate as well as wild-type viruses (160). Because of the lethargy of Δα0 mutants, ICP0 has been held responsible for the establishment of latency and a myriad of other functions. Nevertheless, none of these phenotypic properties of ICP0 correlate directly with the emerging patterns of interaction of ICP0 with cellular proteins—the subject of this review.