© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 73-77,
1998
© 1998 Oxford University Press
Human Herpesvirus 8—the First Human Rhadinovirus
* Affiliation of authors: Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schloßgarten 4, Erlangen, Germany.
Correspondence to: Bernhard Fleckenstein, M.D., Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schloßgarten 4, D-91054 Erlangen, Germany. E-mail: fleckenstein\\{at}viro.med.uni-erlangen.de
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Abstract |
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Kaposi's sarcoma (KS)-associated herpesvirus, also known as human herpesvirus 8 (HHV-8), is the first known human member of the genus Rhadinovirus. It is regularly found by polymerase chain reaction in all forms of KS, in certain types of Castleman's disease, and in body cavity-based B-cell lymphoma. Other members of this virus group occur in nonhuman primates, ungulates, rabbits, and mice and cause in part fulminant lymphomas and other neoplastic disorders of the hematopoietic system. Rhadinoviruses share a typical genome structure; most characteristically, they contain numerous sequences that appear to be sequestered from cellular DNA. We cloned and sequenced almost the complete genome of HHV-8 from a single KS biopsy specimen. Although this procedure revealed collinear organization and extensive homologies with the open reading frames of herpesvirus saimiri, genes with homology to the known oncoproteins (Stp, Tip) were not identified in the HHV-8 genome. However, HHV-8 reading frame K1, the positional analogue of Stp/Tip, was found to be significantly variable between different strains. We found, in addition, the reading frames for homologues of cellular interleukin 6, macrophage inflammatory proteins
and ß (MIP1 and MIP1ß, respectively),
an interferon-responsive factor, and two inhibitors of apoptosis.
Several of these cell-homologous genes of HHV-8 have already been
shown to code for functional proteins.
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Introduction |
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TopAbstractIntroductionReferences |
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Human herpesvirus 8 (HHV-8), also referred to as Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), is the first known human member of the genus Rhadinovirus (1). Members of this group of herpesviruses share a common genome structure: A central segment of low-GC DNA (L-DNA) is flanked by multirepetitive high-GC DNA (H-DNA) (2-6) (Fig. 1)
.
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In addition to their common genome structure, which is the cause of physical properties reflected by the term "rhadinovirus" (
o
[Greek] = fragile), all animal rhadinoviruses
known so far share a common epidemiology. They are frequent in
their natural host (>50%), where infection is not known
to be associated with apparent disease (Table 1). In contrast, infection of closely related species
is often the cause of fulminant lymphoproliferative diseases or
overt malignant lymphoma with fatal outcome. For example, there
is no indication for pathogenic properties of herpesvirus saimiri
in its natural host, the squirrel monkey. However, in related
species (e.g., common marmosets and several other New World
primates), infection by herpesvirus saimiri results in polyclonal
T-cell lymphomas (7). Similarly,
alcelaphine herpesvirus type 1 and the related ovine herpesvirus
type 2 are nonpathogenic in wildebeest and sheep, respectively,
whereas a lymphoproliferative syndrome termed "malignant
catarrhal fever" is caused upon infection of cattle (4). This finding does not necessarily
imply that HHV-8 would be exceptional if it is causing a
malignant tumor in its natural host. The incidence of KS, body
cavity-based lymphomas, and multicentric forms of
Castleman's disease is so low that such disease associations
would have certainly been overlooked in animal models. Likewise,
Epstein-Barr virus (EBV), which is the closest known relative of
HHV-8 in humans, is clearly associated with infectious
mononucleosis and with several cancers. However, primary EBV
infection is usually not apparent unless additional factors, such
as immunosuppression or delay of primary infection, disturb the
delicate balance of virus and host. Infection of species other
than the well-adapted natural host is possibly another example of
an "accident" associated with increased
tumorigenicity.
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Thus, despite the lack of clear-cut evidence for oncogenesis by nonhuman rhadinoviruses in their natural hosts, the finding that infection of non-natural hosts is frequently associated with lymphoproliferative syndromes hints at the pathogenic potential that these viruses might show even in their natural hosts under certain, albeit unusual, circumstances. It has been shown for herpesvirus saimiri that the gene(s) relevant for malignant transformation are located close to the left end of the genome (Fig. 2)
(8-11). A
single reading frame termed "STP-A" is present there
in herpesvirus saimiri subgroup A viruses. This reading frame is
required for the transforming phenotype of herpesvirus saimiri
subgroup A, as shown by deletion mutants (12). Two reading frames, termed "STP-C" and
"TIP," are present at the equivalent position of
herpesvirus saimiri subgroup C viruses, and both are obviously
related to the oncogenic phenotype (10,13). Expression of STP-A in transgenic mice results in lymphoid
tumors (14), whereas animals transgenic
for STP-C develop epithelial tumors (15).
In addition, subgroup C strains of herpesvirus saimiri can
transform human T lymphocytes (16). These
cells still depend on interleukin 2, but the respective T-cell
antigen is no longer required for continuous growth in cell
culture [reviewed in (7)].
Sequencing the complete genome of HHV-8 from both a body
cavity-based lymphoma cell line (5) and a
single KS biopsy specimen has revealed that no obvious homologue
of Stp/Tip or other viral oncogenes is encoded by HHV-8 (5,17). Instead, a reading frame, termed
"K1," is present at the same position in HHV-8 (Figs.
1
and 2). This
reading frame has no detectable sequence homology to STP or other
transformation relevant genes. However, K1 has both a
transmembrane region and a short intracytoplasmic tail like the
transforming genes of other rhadinoviruses that are encoded at
equivalent genomic positions. K1 is thus certainly a candidate
for a transforming gene. Comparison of the two available complete
HHV-8 genomic sequences reveals a striking degree of
conservation. With the possible exception of the very right end
of the unique region, reading frame K1 is by far the most
divergent reading frame. The high degree of interstrain
variability is another feature that K1 shares with the STP genes
of herpesvirus saimiri. Although there is less than 0.1%
divergence between the two complete sequences, 6% of the
amino and nucleic acids are different between the K1 sequences
derived from a KS and a B-cell line. This makes K1 a prime
candidate for studies of HHV-8 molecular epidemiology.
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Acquisition of genes from the host cell genome is a common feature of most herpesviruses and of rhadinoviruses in particular. So far, there are least 14 reading frames of HHV-8 that are clearly homologous to known cellular genes (Table 2).
In contrast to their cellular
counterparts, these viral genes are usually transcribed into an
unspliced messenger RNA. This implies that not genomic DNA
fragments but complementary DNA (cDNA) molecules were integrated
into the viral genome. Reverse transcriptase activity must
therefore have been present. One may speculate that not only was
reverse transcription enabled by co-infection of the same cell by
a retrovirus, but also cellular genes were transferred to the
herpesvirus via retroviral genomes with their capability of
integration. Although different members of the genus Rhadinovirus acquired different genes from the host cell,
these genes are usually found at strikingly similar genomic
positions (Fig. 2). These sequestered
genes are frequently clustered around areas of repetitive
sequence: close to the genomic termini and—most
notably—in two genomic areas about 20-30 kilobase pairs
apart from the ends of the unique region (Fig. 2). The pattern of repetitive elements in these areas
includes stretches rich in AT (adenosine-thymidine) flanked by
elements of dyad symmetry. These are the typical hallmarks of
origins of DNA replication, although experimental data to confirm
this are not available for any of the rhadinoviruses. Therefore,
one scenario for the acquisition of foreign genes by a
herpesvirus is linked to DNA replication. It could well be that,
during replication by the rolling circle mechanism, fragments
arise and, upon re-circularization, cDNA molecules are inserted.
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1 herpesvirus Epstein-Barr
virus (EBV)Although for most of these captured genes it is not very likely that they are essential for virus replication in cell culture, they certainly have important functions in the viruses' natural habitat. Although different rhadinoviruses acquired different host-cell genes, their putative functions apparently converge to achieve three common goals: 1) to enhance DNA replication independently from the cell cycle, 2) to expand the pool of infectable cells, and 3) to counteract the host's responses to infection (18) (Table 3).
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The first function, enhancement of DNA replication independent from the status of the infected cell, is achieved by enzymes of the nucleotide metabolism, i.e., thymidylate synthase, dihydrofolate reductase, and formylglycinoamidine synthase. Virus-encoded cyclins, interleukin 6, and the interleukin 8 receptor may enhance cell proliferation and may thus expand the pool of infectable cells. The three macrophage inflammatory proteins encoded by HHV-8 might work in a similar way by attracting susceptible cells. Apoptosis is a typical response of the host to infection by a virus. HHV-8 carries two genes, ORF16 (vbcl-2) and ORF71 (vFLIP), both of which could extend the life span of infected cells through the inhibition of apoptosis by two different mechanisms (19-21). Similarly, the complement control protein homologues present in most rhadinoviruses counteract the host's response (2,22). The virus-encoded interferon-response factor homologue (vIRF) might fit into this scenario at two different places: 1) It could counteract interferon-mediated suppression, and 2) it could mimic the proliferative effect of human interferon response factor 2. One can easily imagine how these genes can contribute to malignant growth transformation. Increasing the pool of available nucleotides not only enhances viral DNA replication but also facilitates the proliferation of transformed cells (Table 3)
. Genes that
extend the pool of infectable cells or that prolong their life
span, i.e., the virus-encoded cyclins, apoptosis inhibitors,
cytokines, cytokine receptors, and interferon response factors,
could also contribute to dysregulated growth and favor the
development of cancers. Although under normal circumstances the
functions of these viral genes are well balanced with the host,
malignant growth does not occur. Like several other
rhadinoviruses, HHV-8 has a host of genes that could accidentally
contribute to tumor development. Examples of such accidents that
favor malignant growth are infection of a non-natural host (Table
1), infection that occurs usually late in
the host's life, and certainly infection of an
immunosuppressed host. The initially mentioned finding that
rhadinoviruses are not usually pathogenic in their natural host
is therefore still compatible with the likelihood of HHV-8 being
associated with at least two cancers in humans. Diseases as
infrequent as KS, body cavity-based lymphomas, and
Castleman's disease would likely have been overlooked in
animal models. All rhadinoviruses are highly pathogenic only if
certain rare "accidents" coincide with infection, and
infection of a non-natural host by animal rhadinoviruses can be
seen as one example of such an accident, revealing the
facultative pathogenic potential inherent to the rhadinoviruses.
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Acknowledgments |
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Supported by the Ria Freifrau von Firtsch Stiftung, the "Deutsche Krebshilfe—Dr. Mildred Scheel Stiftung" grant No. W134/94/FL2, and European Union grant BMH4-CT95-1016.
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