Infections with high-risk human papillomaviruses (HPVs) are the major risk factor for the development of anogenital cancers. Viral E2 proteins are involved in viral DNA replication and regulation of transcription. Repression of the viral P97 promoter by E2 proteins has been implicated in the modulation of the immortalization capacity and DNA replication properties of high-risk HPVs. Analysis of the cis and trans requirements for repression of the HPV type 31 (HPV31) P97 promoter, however, revealed striking differences between the full-length E2 and the E8ˆE2C fusion protein which were due to conserved residues W6 and K7 of the E8 domain. In contrast to E2, E8ˆE2C completely inhibited the P97 promoter from a single promoter-distal E2 binding site. This novel long-distance repression activity of the E8 domain also enabled E8ˆE2C to inhibit the HPV6a P2 promoter and minimal-promoter constructs containing E2 binding sites. Thus, E8ˆE2C may represent the master repressor of viral gene expression during a high-risk HPV infection, and changes in the activity of E8ˆE2C might contribute to the progression of high-risk HPV-induced lesions.The replication cycle of human papillomaviruses (HPVs) can be divided into two stages. In the basal cell layer of the epidermis, which is composed of division-competent keratinocytes, HPVs establish a persistent, nonproductive infection in which viral DNA genomes are replicated as extrachromosomal elements at low levels and only early viral genes are transcribed. The productive viral replication cycle occurs upon differentiation of infected keratinocytes, which results in highlevel replication of viral genomes, induction of late-gene transcription, and synthesis of infectious virions (22,49).Infections with a subset of HPV types dramatically increase the risk for the development of malignancies of the anogenital tract, and these types have been designated as high-risk HPVs (56,57). Within this group, high-risk HPV type 16 (HPV16), HPV18, and HPV31 have been most intensively studied at the molecular level. Expression of the early E6 and E7 gene products of high-risk HPVs is sufficient to immortalize normal human keratinocytes (NHKs), the natural target cells for HPVs (34). This property is not shared by E6 and E7 genes from low-risk HPV6 and HPV11 and is therefore regarded as being relevant to the carcinogenic potential of high-risk HPVs (34). The exact molecular events that lead to malignant progression of high-risk HPV-induced lesions are still largely unknown.Several lines of evidence suggest that transcriptional modulation of early viral gene expression is a central regulatory event. In the absence of viral gene products, HPV early-gene transcription is activated by a variety of host cell transcription factors, which interact with regulatory sequences located upstream of the major early promoter of high-risk HPV16, -18, and -31, designated P97 for HPV16 and -31 and P105 for HPV18 (22). The basal activity of HPV early promoters can be further modulated by viral E2 proteins, which are s...
Carcinogenic DNA viruses such as high-risk human papillomaviruses (HPV) and Epstein-Barr-Virus (EBV) replicate during persistent infections as low-copy-number plasmids. EBV DNA replication is restricted by host cell replication licensing mechanisms. In contrast, copy number control of HPV genomes is not under cellular control but involves the viral sequence-specific DNA-binding E2 activator and E8 ∧ E2C repressor proteins. Analysis of HPV31 mutant genomes revealed that residues outside of the DNA-binding/dimerization domain of E8 ∧ E2C limit viral DNA replication, indicating that binding site competition or heterodimerization among E2 and E8∧ E2C proteins does not contribute to copy number control. Domain swap experiments demonstrated that the amino-terminal 21 amino acids of E8 ∧ E2C represent a novel, transferable DNA replication repressor domain, whose activity requires conserved lysine and tryptophan residues. Furthermore, E8∧ E2C(1-21)-GAL4 fusion proteins inhibited the replication of the plasmid origin of replication of EBV, suggesting that E8 ∧ E2C functions as a general replication repressor of extrachromosomal origins. This finding could be important for the development of novel therapies against persistent DNA tumor virus infections.DNA viruses such as certain types of human papillomaviruses (HPV) and Epstein-Barr-virus (EBV), a member of the human herpesvirus family, are of major clinical interest because infections with these viruses have been linked to the development of human malignancies. HPV types 16, 18, 31, and 45 represent the predominant etiological agents of cervical cancer, and EBV infection has been suggested to contribute to the development of a number of lymphomas and nasopharyngeal carcinoma (28,42,43). Both HPV and EBV replicate as extrachromosomal elements in the nucleus of human cells. Interestingly, papillomaviruses and EBV maintain their genomes at defined copy numbers (10 to 50 virus copies per EBV-infected cell and 100 virus copies per papillomavirusinfected cell) in cultured cells over long periods of time (1,3,10,16,39,40). This behavior in tissue culture is thought to reflect viral DNA replication during persistent infections in vivo.In the latent phase, EBV DNA replication initiates at oriP, whereas in the lytic (productive) phase, oriLyt is responsible for the replication of EBV DNA (12,40). In contrast to oriLyt, the activity of oriP requires the viral EBNA1 protein, and viral copy number is kept constant by host cell replication licensing mechanisms, which ensure that eukaryotic genomes are copied exactly once before cell division (1, 40, 41). Most likely, this is achieved by recruiting the human origin recognition complex to oriP (5,8,31).Papillomaviruses use a different strategy to successfully maintain their DNA at defined copy numbers. In contrast to oriP, papillomavirus origins are not subject to replication licensing, but appear to use copy number control mechanisms, which are not fully understood (10). Two viral proteins are essential for the activation of papilloma...
Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage.
Human parvovirus B19 (B19V) DNA is highly prevalent in endothelial cells lining up intramyocardial arterioles and postcapillary venules of patients with chronic myocarditis and cardiomyopathies. We addressed the question of a possible stimulation of B19V gene expression in endothelial cells by infection with adenoviruses. Adenovirus infection led to a strong augmentation of B19V structural and nonstructural proteins in individual endothelial cells infected with B19V or transfected with an infectious B19V genome. Transactivation was mostly mediated at the level of transcription and not due to adenovirus-mediated induction of second-strand synthesis from the single-stranded parvoviral genome. The main adenoviral functions required were E1A and E4orf6, which displayed synergistic effects. Furthermore, a limited B19V genome replication could be demonstrated in endothelial cells and adenovirus infection induced the appearance of putative dimeric replication intermediates. Thus the almost complete block in B19V gene expression seen in endothelial cells can be abrogated by infection with other viruses.
We thus conclude that B19V infection has a direct VP2-mediated negative impact on trafficking of CAC in the presence of impaired cardiac regeneration.
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