© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 65-71,
1998
© 1998 Oxford University Press
Kaposi's Sarcoma-Associated Herpesvirus-Encoded Oncogenes and Oncogenesis
* Affiliations of authors: P. S. Moore (School of Public Health), Y. Chang (Department of Pathology, College of Physicians and Surgeons), Columbia University, New York, NY.
Correspondence to: Patrick S. Moore, M.D., Department of Pathology, Columbia University, 630 W. 168th St., New York, NY 10032.
 |
Abstract |
|---|
 Top Abstract IntroductionReferences |
|---|
Molecular biologic studies of Kaposi's sarcoma-associated herpesvirus (KSHV) have identified a number of potential viral oncogenes that may contribute to KSHV-related neoplasia including a D-type cyclin, an IL-6-like cytokine, and a novel member of the interferon regulatory factor family. KSHV is functionally related to other DNA tumor viruses by encoding specific proteins to inhibit pRb, pro-apoptotic, and interferon-signaling tumor suppressor pathways. The virus appears to employ molecular piracy of cellular regulatory genes as a mechanism to avoid cellular antiviral responses. The transparency of the KSHV genome allows ready identification of the cellular regulatory pathways which may be involved in transformation by KSHV. This provides strong support to the notion that some tumor suppressor pathways serve the dual function of being antiviral pathways to induce cell cycle arrest, apoptosis, and enhanced cell-mediated immunity in response to virus infection. Neoplasia may result from specific viral strategies to overcome these host defense pathways.
|
Introduction |
|---|
|
TopAbstractIntroductionReferences |
|---|
The second full year of working with Kaposi's sarcoma-associated herpesvirus (KSHV) is now finished and scientific studies on this virus are rapidly maturing. With the publication of the full-length genomic sequence (1), new opportunities to investigate its molecular biology and virology are becoming available. This review will try to provide a road map for subsequent papers in this symposium on the major features of the KSHV genome and its potential oncogenes. Despite the early stage of KSHV molecular biologic studies, the virus is already providing unique insights into tumorigenesis and may serve as an important model for virus-induced oncogenesis.
The evidence gathered to date is overwhelming in support of KSHV as the infectious cause of Kaposi's sarcoma (KS) (2). A review of 21 published studies involving 549 patients, with all forms of Kaposi's sarcoma from various parts of the world, shows that KSHV DNA can be detected on average 95% of the time in KS lesions by polymerase chain reaction. This exceeds the positivity rate for detection of papillomavirus in cervical cancer (3). It is now clearly established using a variety of techniques that KSHV are not only localized to KS lesions (4-6), but that viral DNA and RNA are detectable in most KS tumor spindle cells (7-9).
Newly developed KSHV serologic assays also support a causal role for the virus in KS. As discussed by Weiss (10), published assays show similar epidemiologic trends, despite important differences in their sensitivities and specificities. The relative KSHV seroprevalence measured by these assays matches the patterns for KS risk groups among patients with acquired immunodeficiency syndrome (AIDS) (11-17) and the patterns for non-HIV-related KS incidence among patients from various countries (15,16,18). For KSHV to be causally related to KS, infection must precede onset of disease. This is an absolute criteria for causality, and both seroconversion (13,18-20) and DNA-based (21,22) detection studies provide evidence for KSHV infection among most AIDS-KS patients prior to disease onset.
Taken together, these and other studies (23-26) now indicate that KSHV is not a ubiquitous infection in most human populations, although high rates of infection in some populations [e.g., Italians and Ugandans (18)] may account for early studies suggesting widespread human KSHV infection (27,28). It is thus likely that the virus is a necessary, but not necessarily sufficient cofactor for KS development. This does not diminish the role of KSHV in the genesis of KS and related neoplasias. With the possible exceptions of rabies and HIV, no infectious syndrome or illness is solely due to infection by a single agent without contributing host or environmental risk factors. Similarly, asymptomatic infection is the norm for most infectious agents and only a minority of persons infected with KSHV should be expected to eventually develop KS. This relatively simple view of KS causation has become complicated by the recent finding of KSHV in cultured multiple myeloma stromal cells (29). Whether or not this association with multiple myeloma, a cancer with a very different epidemiologic presentation from KS, is real remains an area for future research.
The important questions now become "How does KSHV cause KS, and what is the relative contribution of the virus to tumorigenesis vis-à-vis immunosuppression and other predisposing factors?" As indicated by Blackbourne et al. (30), techniques have not yet been developed to allow in vitro high-titered virus transmission to other cell lines (11,31). Therefore, much of the work on KSHV-related tumorigenesis and cell transformation has had to rely on molecular biologic investigation of individual genes. Like other herpesviruses, KSHV is presumed to replicate as a circular episome in latently infected cells and is packaged in a linear genomic form during lytic replication. The importance of this is that standard dogma tells us lytic replication is uniformly fatal to the cell and that lytic phase gene expression cannot contribute to tumorigenesis. However, recent findings on lytic KSHV replication in KS lesions and the effects of viral DNA polymerase inhibitors on clinical disease suggest that we should carefully question this assumption (8,32-34). As indicated by Ganem (35), it is possible that a minority population of lytically infected cells is important in sustaining the KS lesion by constantly recruiting new, infected tumor cells directly or through paracrine mechanisms.
The KSHV genome was first determined by Renne et al. (36) to be approximately 165-kb long using purified
virion-banded DNA (36). This has been
confirmed through genome mapping and sequencing studies (1). We had previously estimated the genome
size to be as large as 270 kb (11), but
this was determined using the BC-1 cell line which has a large
genomic duplication (1). The long unique
region (LUR), approximately 140 kb in length, comprises the
entire coding region for the virus and encodes at least 81 genes
(Fig. 1).
|
Because of the high level of synteny between KSHV and herpesvirus saimiri (HVS, the prototypical member of the genus Rhadinovirus), KSHV genes are named after their corresponding HVS homologs starting from the left hand end of the genome. KSHV is missing the first three genes found in HVS (37) and the first homolog to a HVS gene begins at ORF 4. Synteny with HVS (except for ORFs 2 and 70) extends throughout the genome up to ORF 75 located on the right end of the LUR. Genes having detectable homology to HVS genes include structural protein and DNA synthetic enzyme genes which are conserved among all herpesviruses.
There are a number of genes, however, which are not found in HVS and are given a K designation (ORFs K1-15). No KSHV genes with sequence homology to the EBV Epstein-Barr nuclear antigens, latent membrane proteins, or the HVS saimiri transforming proteins involved in cell transformation are found in KSHV. Over 90% of the LUR (excepting approximately 12 kb on the right-hand portion of the genome) has also been recently sequenced from a KS lesion by Bernard Fleckenstein's group. While details of this sequencing project have not yet been published, comparison of the deposited KS lesion Genbank sequence to the BC-1 sequence (1) shows a remarkable degree of sequence conservation between BC-1 and KS isolates (generally <0.1% divergence), confirming previous comparisons (11). Sequence divergence is most pronounced at the K1 locus and in internal repeat regions (e.g., Frnk, Vnct, Zppa, and Moi). The right end sequence has proven particularly difficult to clone into sequencing vectors (1) and it is unknown whether this part of the genome contains a hypervariable region similar to the left hand K1 locus.
Fig. 2 shows a simplified schematic
diagram of the genome demonstrating the conserved herpesvirus
gene blocks as first described by Chee et al. (38) from their sequencing of the cytomegalovirus
genome. Genes that are conserved among members of all three
herpesvirus subfamilies lie within these blocks. In between
conserved gene blocks are regions that are unique to KSHV or are
also found only in other rhadinoviruses. The unique regions
contain a remarkable array of cellular gene homologs, encoding
proteins involved in cell cycle regulation or cell signaling (1,39). In addition, some DNA synthetic
enzymes, such as dihydrofolate reductase (DHFR) and thymidylate
synthase (TS), are encoded in these regions. Cellular homologs to
the DNA synthetic enzymes encoded by the virus are under the
control of the E2F transcriptional factor family (40), suggesting that the virus has pirated those DNA
synthesis genes that will allow it to replicate DNA outside of
the S phase of the cell cycle. Two additional genes found in
unique regions include the T1.1 and T0.7 (ORF K12) genes encoding
polyadenylated transcripts (41-43) used
for in situ hybridization studies because of their
abundance in infected cells (8).
|
What are the possible reasons for the virus having these cellular homologs? Our working hypothesis is that these viral proteins provide a defense against stereotypic cellular responses to viral infection. When a cell is infected by a virus it undergoes cell cycle shutdown, induction of apoptosis and in vivo enhancement of cell-mediated immunity through increased major histocompatibility antigen presentation [reviewed in (44)]. These effects may be in part mediated by retinoblastoma (pRb) and p53 tumor suppressor pathways, which are involved in the control of dysregulated cellular division (45) and, possibly, unregulated viral nucleic acid replication.
The cell cycle is regulated at the G1 checkpoint by the E2F family of transcriptional factors that initiate transcription of a number of enzymes involved in DNA synthesis, allowing the cell to pass into the S phase of the cell cycle. Nonphosphorylated retinoblastoma protein binds to E2F preventing E2F directed transcription and stops the cell from progressing through the S phase of the cell cycle (46,47). This can be abrogated by the activity of D-type cyclins interacting with various cyclin-dependent kinases, such as CDK6, which form a complex that phosphorylates pRb, causing release of active E2F, and allowing transcription of DNA synthesis genes.
p21 and related cyclin-dependent kinase inhibitors act as a
counterbalance to the cyclin-CDK complex, preventing pRb
phosphorylation and inhibition. Under conditions where
retinoblastoma protein is mutated or when specific pRb inhibitors
are present, such as adenovirus E1A, the cell can progress
through the G1 checkpoint in an uncontrolled fashion.
A feedback mechanism exists (48), however,
such that overexpression of active E2F results in p53 activation
that induces either transcription of p21 to reinitiate control of
the cell cycle (49) or, failing this,
induction of p53-mediated apoptosis (50,51) (Fig. 3).
|
This is a very simplified, and only to some degree correct, explanation of how these two tumor suppressor pathways interact with each other, but it is apparent that both tumor suppressor pathways are likely to act as antiviral pathways as well. A number of viruses have evolved specific gene products to inhibit both the pRb and p53 activation (52-54). Growth suppression imposed by pRb activity is a probable means of limiting replication of the naked DNA episomes of a latent, infecting virus. Adenovirus, for instance, encodes E1A which specifically inhibits pRb interactions with E2F to prevent G0 arrest. However when E1A is expressed in an unopposed fashion, p53-mediated apoptosis is initiated. Adenovirus also encodes the antiapoptotic E1B19k and E1B55k proteins preventing p53-induced apoptosis. An important illustration of this counterbalance is seen with engineered adenovirus mutants that lack functional E1B genes and are only capable of replicative growth in p53-deficient tumor cells (55). A similar, although phylogenetically and mechanistically distinct, interaction occurs for the papillomavirus E7 and E6 proteins with pRb and p53 pathways. Latent EBV gene expression may have a similar effect on these tumor suppressor pathways: work from Kieff's group (56-58) and others (59) demonstrates the potential antiapoptotic role of LMP1 in B cells, and data suggest that EBNA2 and EBNA-LP may interact to induce cyclin D2 overexpression (60).
How does KSHV fit into this pattern? Like adenoviruses and
papillomaviruses, KSHV also possesses a specific inhibitor of pRb
function. KSHV directly encodes a homolog to D-type cyclins,
v-cyc, on the right end of the genome at ORF72 (61,62). ORF73, which encodes the major latency expressed
antigen LANA (9), and ORF74, which encodes
an IL-8-like receptor that can induce cellular proliferation (61,63), also lie in this region of the
genome. v-cyc has been shown to be functionally active in
phosphorylating pRb at authentic sites through interactions with
cdk6 (62), but it may also have broader
specificity than cellular D-type cyclins in that it can mediate
phosphorylation of histone H1 as well (64,65). The altered substrate specificity of the viral
cyclin suggests that it may act at other stages of the cell cycle
in addition to the G1/S checkpoint (Fig. 3
).
With an active viral cyclin inhibiting pRb activity, one could also expect that there should be a counterbalancing anti-apoptotic set of genes expressed by KSHV. Indeed, KSHV v-cyc overexpression in NIH3T3 cells rapidly induces cell death presumably through p53-mediated apoptosis (Boshoff C, Sarid R: unpublished observation). Not surprisingly, there are a number of KSHV genes that can potentially prevent cellular apoptosis. For example, the virus encodes a functional IL-6-like cytokine (ORF K2) which prevents B9 cell apoptosis (39,66,67) and is expressed only in KSHV hematopoietic cells, not KS tumor cells (39). The vIL-6 appears to induce appropriate IL-6 Jak-STAT pathway activation [although its receptor specificity is different from hu-IL-6 (68)] and is thus likely to also induce antiapoptotic bcl-xL protein production (69).
KSHV also encodes a bcl-2 homologue (ORF16) simultaneously discovered by our group (70) and Cheng et al. (71) that has functional anti-apoptotic activity in both yeast and mammalian cells. There is disagreement as to whether or not v-bcl-2 heterodimerizes with cellular members of the bax-bcl-2 family, but it is clear that the KSHV v-bcl-2 prevents bax-mediated apoptosis. More recently, Thome et al. (72) have identified FLICE inhibiting proteins (v-FLIP) encoded by rhadinoviruses that possess dominant negative DEDD domains to inhibit apoptosis induced by CD95 pathway activation. No functional studies have been published yet on the corresponding KSHV protein (ORF K13), but it is an intriguing protein since it is expressed during viral latency in PEL and KS tumors, along with ORF72 and ORF73 (Sarid R, Wiezorek J, Moore PS, Chang Y: unpublished observation). It is not known whether or not v-FLIP has downstream activity that might cause inhibition of tumor suppressor pathway apoptosis. We are at an early stage in understanding the interplay of these KSHV proteins with known tumor suppressor pathways, but it is not unreasonable to suppose that these proteins either singly or in combination are active in preventing apoptosis induced by KSHV-inhibition of pRb.
In addition to cell cycle shutdown and apoptosis, enhanced immune recognition is another important cellular defense against virus infection. Many of these antiviral effects are coordinated at the cellular level through interferon signal regulation. We have found one KSHV protein involved in immune regulation, the v-IRF encoded by ORF K9 (39), which may have a unique mechanism for allowing KSHV to escape immune surveillance (73). This gene actually has a relatively low degree of sequence homology with the family of interferon regulatory factors (IRF) involved in positively or negatively regulating interferon signal transduction (74).
Interferon-ß binding at its receptor induces activation
through the Jak-STAT signaling pathway with the formation of a
trimeric complex of phosphorylated STAT1, STAT2, and p48 (or
ISGF3
) (75,76). This complex, called
interferon-stimulated gene factor 3 (ISGF3), translocates to the
nucleus and binds to enhancer elements (ISREs) in promoters of
interferon-stimulated genes. Interferon-induced gene
transcription effects the phenotypic changes associated with
interferon stimulation of cells, including increased MHC I
transcription (77,78), shut down of the
cell cycle [through transcription of the cyclin-dependent
kinase inhibitor p21 (79-81)], and
also possibly p53-independent apoptosis (82). Interferon also induces expression of the
interferon regulatory factors IRF1 and IRF2 which also bind to
ISRE. IRF1 probably initiates an amplifying loop that markedly
amplifies the interferon signal whereas the more slowly degraded
IRF2 shuts off this amplification cascade by competitive
inhibition at ISRE sites. Thus, it is apparent that cellular
proliferation control is modulated by interferon-mediated immune
signaling (74,83).
KSHV vIRF inhibits IFN-ß signal transduction in a specific and dose-dependent fashion as measured by an ISRE-containing CAT reporter construct (73). Further, vIRF transfection prevents IFNß-induced transcription of the cyclin-dependent kinase inhibitor p21 suggesting a possible effect on cell cycle regulation. Expression of vIRF in NIH3T3 cells induces full cellular transformation and vIRF-expressing NIH3T3 cells form tumors when injected into nude mice. vIRF appears to have highly reproducible oncogenic activity in the NIH3T3 assay; however, these data should be interpreted to suggest only that this gene is active in cellular proliferation. It is unlikely that vIRF expression alone is responsible for KSHV-related human tumor formation and it is more likely to be only one component contributing to a multigenic process (73).
Despite the early stage of molecular studies on KSHV, a
functional comparison to other DNA tumor viruses is now
reasonable (Table 1). Like other DNA tumor
viruses, KSHV encodes specific proteins that are candidates for
overcoming pRb-mediated growth arrest and p53-mediated apoptotic
activity. Further, like the E1A protein of adenoviruses (84,85), vIRF may specifically abrogate
interferon-mediated responses, contributing to tumor induction as
well. There is a close correlation between the cellular genes
induced by EBV and the genes pirated by KSHV (1) suggesting that both herpesviruses modify their
cellular environments in similar ways: KSHV brings in its own
cellular homologs into the cell whereas EBV induces cellular
genes to modify regulatory pathways essential to its survival.
Whether additional common tumor virus pathways contributing to
cell transformation will be found remains to be seen.
|
By examining the KSHV genome, a number of potential oncogenes have been identified by sequence homology alone. This does not necessarily mean that they function as transforming oncogenes in vivo and care is needed not to overinterpret the results of isolated gene studies. Primary effusion (or body cavity-based) lymphomas are clearly outgrowths of malignant clones (86) and provide a model for cell transformation caused in part, or entirely, by viral oncogene expression. KS, however, is a complex tumor whose origins remain disputed. In one view, KS may result from hyperplastic cellular proliferation driven by exogenous cytokines while an opposing view holds that it may result from KSHV oncogene-driven cellular proliferation. Recent HUMARA (87,88) and KSHV terminal repeat analyses (1) provide evidence for a clonal proliferation of tumor cells in KS lesions and support the latter supposition although these findings are not universally accepted (89,90). This is further complicated by the fact that cell clonality does not necessarily result from virus-driven cell proliferation since transformed cells could originate from multiple virus-infected loci. In addition, KSHV encodes secreted cytokines (39) which are likely to play a role in non-neoplastic disorders, such as Castleman's disease (91,92). This debate need not be polarizing, since it is likely that both paracrine and endogenous viral factors will ultimately be found to contribute to KS pathogenesis.
Additionally, in vivo expression of potential KSHV-encoded oncogenes is critical to understanding their contribution to these neoplastic disorders. Some genes, such as vIL-6, are expressed in infected hematopoietic tissues but not KS lesions. Other genes, such as the v-bcl-2 may only be expressed during lytic cycle replication (70) and are less likely to contribute to cellular transformation. Finally, isolated gene studies do not take into consideration immune surveillance, which we already know is likely to be tremendously important for this virus since KS is primarily a disease occurring in severely immunosuppressed patients.
Because of the early stage of KSHV, the list of oncogenes and their interactions is almost certainly incomplete. The growth- promoting ability of other viral proteins, such as the GPCR (93), the MIP homologs (94), and K1 (Jung J: personal communication), is an active area of investigation and promises a rich source of information on cell-virus interactions. Beyond providing pathogenic insights into KS and primary effusion lymphomas, KSHV is an important new model virus-induced tumorigenesis. KSHV appears to be another example of a tumor virus which is well-adapted to its host and causes tumors primarily in altered or "accidental" environments. Most tumor viruses cause tumors only under conditions where there is immunosuppression, complementing mutations in host cells, or during infection of non-native hosts. It is difficult to imagine the evolutionary benefit for the virus to cause a tumor in which it replicates latently and is therefore nontransmissible, which may kill the host. In the setting of severe AIDS-related immunosuppression, however, KSHV appears to be an extremely potent inducer of tumor formation. Early in the AIDS epidemic, up to 50% of gay male AIDS patients eventually developed KS (93) suggesting an extraordinarily high rate of tumor development among those persons who were both KSHV-infected and immunocompromised.
The convergent evolution of DNA tumor viruses to inhibit similar tumor suppressor pathways by different mechanisms suggests that these pathways also serve antiviral functions. Tumor viruses apparently require a mechanism for inhibiting tumor suppressor pathways if they are to survive as a latent episome in an actively dividing cell. It should not be surprising for cells to use tumor suppressor pathways to control both cancer cell growth and viral replication since both cases involve control of dysregulated DNA replication. Careful examination of KSHV and other tumor viruses will continue to lead to new insights into mechanisms of nonviral carcinogenesis.
Ready identification of regulatory gene homologs encoded by KSHV gives this virus a unique degree of transparency. Despite its complex interaction with cellular regulatory pathways, KSHV's option to use molecular piracy provides accessible starting points for examining these pathways. The extensive degree of symmetry between genes encoded by KSHV and those induced by EBV (1) also indicates that insights gained from one virus may to some degree be transferable to the other. KSHV illustrates in a new fashion that several major cellular pathways preventing tumor outgrowth, such as the p53 and pRb pathways, may also guard against latent virus infection. Virus strategies to overcome these intracellular defenses appear to inadvertently contribute to cell transformation. KSHV may thus provide a new, unique, and tractable model for exploring these and other issues in viral oncogenesis.
|
Acknowledgments |
|---|
Supported by Public Health Service grant CA67391 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
We thank the members of our laboratory who have contributed to the projects briefly described here, including Roy Bohenzky, Shou-Jiang Gao, Sonja Olsen, Ronit Sarid, and Jeffrey Wiezorek. We would also like to acknowledge the contributions of our collaborators, especially Drs. Robin Weiss and Chris Boshoff of the Institute for Cancer Research, James Russo and Izzy Edelman of the Columbia Genome Center, and Thomas Schulz from the University of Liverpool. We also thank Laurie Anderson for her help in preparing this manuscript.
|
References |
|---|
|
TopAbstractIntroductionReferences |
|---|
1
Russo JJ, Bohenzky RA, Chien MC,
Chen J, Yan M, Maddalena D, et al. Nucleotide sequence of the
Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl
Acad Sci U S A 1996;93:14862-7.
2 Olsen SJ, Moore PS. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) and the etiology of KS. In: Freidman H, Medveczky P, Bendinelli M, editors. Molecular immunology of herpesviruses. New York: Plenum Press. In press.
3 IARC: Human Papillomaviruses. In: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (IARC, ed). Lyon, France, 1995:90-233.
4
Lebbe C, Agbalika F, de CP,
Deplanche M, Rybojad M, Masgrau E, et al. Detection of human
herpesvirus 8 and human T-cell lymphotropic virus type 1
sequences in Kaposi sarcoma. Arch Dermatol 1997;133:25-30.
5 Dupin N, Grandadam M, Calvez V, Gorin I, Aubin JT, Harvard S, et al. Herpesvirus-like DNA in patients with Mediterranean Kaposi's sarcoma. Lancet 1995;345:761-2.[CrossRef][Web of Science][Medline]
6
Moore PS, Chang Y. Detection of
herpesvirus-like DNA sequences in Kaposi's sarcoma lesions
from persons with and without HIV infection. N Engl J Med 1995;332:1181-5.
7 Boshoff C, Schulz TF, Kennedy MM, Graham AK, Fisher C, Thomas A, et al. Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med 1995;1:1274-8.[CrossRef][Web of Science][Medline]
8 Staskus KA, Zhong W, Gebhard K, Herndier B, Wang H, Renne R, et al. Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J Virol 1997;71:715-9.[Abstract]
9 Rainbow L, Platt GM, Simpson GR, Sarid R, Gao SJ, Stoiber H, et al. The 226- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is encoded by ORF73 and is a component of the latency-associated nuclear antigen. J Virol 1997;71:5915-21.[Abstract]
10 Boshoff C, Talbot S, Whitby D, Reeves J, Weiss RA. AIDS-associated tumors and HHV8. In: National AIDS Malignancy Conference. Bethesda (MD), 1997:A13.
11 Neipel F, Albrecht JC, Fleckenstein B. Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J Virol 1977;71:4187-92. [Web of Science][Medline]
12
Miller G, Rigsby MO, Heston L,
Grogan E, Sun R, Metroka C, et al. Antibodies to
butyrate-inducible antigens of Kaposi's sarcoma-associated
herpesvirus in patients with HIV-1 infection. N Engl J Med 1996;334:1292-7.
13
Gao SJ, Kingsley L, Hoover DR,
Spira TJ, Rinaldo CR, Saah A, et al. Seroconversion to antibodies
against Kaposi's sarcoma-associated herpesvirus-related
latent nuclear antigens before the development of Kaposi's
sarcoma. N Engl J Med 1996;335:233-41.
14 Kedes DH, Operskalski E, Busch M, Kohn R, Flood J, Ganem D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat Med 1996;2:918-24.[CrossRef][Web of Science][Medline]
15 Simpson GR, Schulz TF, Whitby D, Cook PM, Boshoff C, Rainbow L, et al. Prevalence of Kaposi's sarcoma associated herpesvirus infection as measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 1996;348:1133-8.[CrossRef][Web of Science][Medline]
16 Lennette ET, Blackbourne DJ, Levy JA. Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet 1996;348:858-61.[CrossRef][Web of Science][Medline]
17
Kedes DH, Ganem D, Ameli N,
Bacchetti P, Greenblatt R. The prevalence of serum antibody to
human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) among
HIV-seropositive and high-risk HIV-seronegative women. JAMA 1997;277:478-81.
18 Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, Ziegler J, et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med 1996;2:925-8.[CrossRef][Web of Science][Medline]
19 Andre S, Schatz O, Bogner JR, Zeichhardt H, Stoffler MM, Jahn HU, et al. Detection of antibodies against viral capsid proteins of human herpesvirus 8 in AIDS-associated Kaposi's sarcoma. J Mol Med 1997;75:145-52.[CrossRef][Web of Science][Medline]
20
Parravicini C, Olsen SJ, Capra M,
Poli F, Sirchia G, Gao SJ, et al. Risk of Kaposi's
sarcoma-associated herpesvirus transmission from donor allografts
among Italian posttransplant Kaposi's sarcoma patients. Blood 1997;90:2826-9.
21 Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, et al. Detection of Kaposi's sarcoma-associated herpesvirus (KSHV) in peripheral blood of HIV-infected individuals predicts progression to Kaposi's sarcoma. Lancet 1997;364:799-802.
22 Moore PS, Kingsley L, Holmberg SD, Spira T, Conley LJ, Hoover D, et al. Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma. AIDS 1996;10:175-80.[Web of Science][Medline]
23 Corbellino M, Bestetti G, Galli M, Parravicini C. Absence of HHV-8 in prostate and semen [letter]. N Engl J Med 1996;335:1238-9.
24 Howard MR, Whitby D, Bahadur G, Suggett F, Boshoff C, Tenant FM, et al. Detection of human herpesvirus 8 DNA in semen from HIV-infected individuals but not healthy semen donors. AIDS 1997;11:F15-F19.[CrossRef][Web of Science][Medline]
25
Dupin N, Gorin I, Escande JP,
Calvez V, Grandadam M, Huraux JM, et al. Lack of evidence of any
association between human herpesvirus 8 and various skin tumors
from both immunocompetent and immunosuppressed patients. Arch Dermatol 1997;133:537-7.
26 Boshoff C, Talbot S, Kennedy M, O'Leary J, Schulz T, Chang Y. HHV8 and skin cancers in immunosuppressed patients [letter] [published erratum appears in Lancet 1996;348:138]. Lancet 1996;347:338-9.[Web of Science][Medline]
27
Monini P, de Lellis L, Fabris M,
Rigolin F, Cassai E. Kaposi's sarcoma-associated herpesvirus
DNA sequences in prostate tissue and human semen. N Engl J
Med 1996;334:1168-72.
28 Monini P, de Lellis L, Cassai E. Absence of HHV-8 in prostate and semen [letter]. N Engl J Med 1996;335:1238-9.
29
Rettig MB, Ma HJ, Vescio RA, Pold
M, Schiller G, Belson D, et al. Kaposi's sarcoma-associated
herpesvirus infection of bone marrow dendritic cells from
multiple myeloma patients. Science 1997;276:1851-4.
30 Blackbourne DJ, Lennette E, Mourich D, Witte M, Way D, Nelson J, et al. Host range studies of human herpesvirus 8 (HHV8). In: National AIDS Malignancy Conference. Bethesda (MD), 1997:A34.
31
Foreman KE, Friborg JJ, Kong WP,
Woffendin C, Polverini PJ, Nickoloff BJ, et al. Propagation of a
human herpesvirus from AIDS-associated Kaposi's sarcoma. N Engl J Med 1997;336:163-71.
32
Jones J, Peterman T, Chu S, Jaffe
H. AIDS-associated Kaposi's sarcoma. Science 1995;267:1078-9.
33 Mocroft A, Youle M, Gazzard B, Morcinek J, Halai R, Phillips AN. Anti-herpesvirus treatment and risk of Kaposi's sarcoma in HIV infection. AIDS 1996;10:1101-5.[Web of Science][Medline]
34 Herndier B, Shiramizu B, Weinstein M, Ganem D, Orenstein JM. KSHV latent and lytic infection in Kaposi's sarcoma lesions and lymphoid tissue. In: National AIDS Malignancy Conference. Bethesda (MD), 1997.
35 Ganem D. Latent and lytic replication of HHV-8/KSHV. In: National AIDS Malignancy Conference. Bethesda (MD), 1997.
36 Renne R, Lagunoff M, Zhong W, Ganem D. The size and conformation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 1996;70:8151-4.[Abstract]
37
Albrecht JC, Nicholas J, Biller D,
Cameron KR, Biesinger B, Newman C, et al. Primary structure of
the Herpesvirus saimiri genome. J Virol 1992;66:5047-58.
38 Chee MS, Bankier SB, Bohni CM, Brown RC, Horsnell T, Hutchison CA, et al. Analysis of the protein coding content of the sequence of cytomegalovirus strain AD169. Curr Top Microbiol Immunol 1990;154:125-69.[Web of Science][Medline]
39
Moore PS, Boshoff C, Weiss RA,
Chang Y. Molecular mimicry of human cytokine and cytokine
response pathway genes by KSHV. Science 1996;274:1739-44.
40 Adams PD, Kaelin WJ. Transcriptional control by E2F. Semin Cancer Biol 1995;6:99-108.[CrossRef][Web of Science][Medline]
41
Sun R, Lin SF, Gradoville L, Miller
G. Polyadenylated nuclear RNA encoded by Kaposi
sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 1996;93:11883-8.
42 Zhong WD, Ganem D. Characterization of ribonucleoprotein complexes containing an abundant polyadenylated nuclear RNA encoded by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8). J Virol 1997;71:1207-12.[Abstract]
43
Zhong W, Wang H, Herndier B, Ganem
D. Restricted expression of Kaposi sarcoma-associated herpesvirus
(human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl
Acad Sci U S A 1996;93:6641-6.
44 Shen Y, Shenk TF. Viruses and apoptosis. Curr Opin Genet Devel 1995;5:105-11.[CrossRef][Medline]
45 Weinberg RA. The cat and mouse games that genes, viruses, and cells play. Cell 1997;88:573-5.[CrossRef][Web of Science][Medline]
46 Sherr CJ. D-type cyclins. Trends Biochemical Sci 1995;20:187-90.[CrossRef][Web of Science][Medline]
47
Sherr CJ. Cancer cell cycles. Science 1996;274:1672-7.
48 White E. Tumour biology. p53, guardian of Rb. Nature 1994;371:21-2.[CrossRef][Medline]
49 Michieli P, Li W, Lorenzi MV, Miki T, Zakut R, Givol D, et al. Inhibition of oncogene-mediated transformation by ectopic expression of p21Waf1 in NIH3T3 cells. Oncogene 1996;12:775-84.[Web of Science][Medline]
50
Wu X, Levine AJ. p53 and E2F-1
cooperate to mediate apoptosis. Proc Natl Acad Sci U S A 1994;91:3602-6.
51 Hiebert SW, Packham G, Strom DK, Haffner R, Oren M, Zambetti G, et al. E2F-1:DP-1 induces p53 and overrides survival factors to trigger apoptosis. Mol Cell Biol 1995;15:6864-74.[Abstract]
52 White E. Regulation of p53-dependent apoptosis by E1A and E1B. Curr Top Microbiol Immunol 1995;199:34-58.
53 Teodoro JG, Branton PE. Regulation of apoptosis by viral gene products. J Virol 1997;71:1739-46.[Web of Science][Medline]
54 Farthing AJ, Vousden KH. Functions of human papillomavirus E6 and E7 oncoproteins. Trends Microbiol 1994;2:170-4.[CrossRef][Medline]
55
Bischoff JR, Kirn DH, Williams A,
Heise C, Horn S, Muna M, et al. An adenovirus mutant that
replicates selectively in p53-deficient human tumor cells. Science 1996;274:373-6.
56 Kieff E. Viral-mediated mechanisms of cancer pathogenesis. In: National AIDS Malignancy Conference. Bethesda (MD), 1997.
57 Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 1995;80:389-99.[CrossRef][Web of Science][Medline]
58
Kieff E. Epstein-Barr
virus—increasing evidence of a link to carcinoma
[editorial]. N Engl J Med 1995;333:724-6.
59 Okan I, Wang Y, Chen F, Hu LF, Imreh S, Klein G, et al. The EBV-encoded LMP1 protein inhibits p53-triggered apoptosis but not growth arrest. Oncogene 1995;11:1027-31.[Web of Science][Medline]
60 Sinclair AJ, Palmero I, Peters G, Farrell PJ. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO J 1994;13:3321-8.[Web of Science][Medline]
61 Cesarman E, Nador RG, Bai F, Bohenzky RA, Russo JJ, Moore PS, et al. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J Virol 1996;70:8218-23.[Abstract]
62 Chang Y, Moore PS, Talbot SJ, Boshoff CH, Zarkowska T, Godden-Kent D, et al. Cyclin encoded by KS herpesvirus. Nature 1996;382:410.[CrossRef][Medline]
63 Arvanitakis L, Geras RE, Varma A, Gershengorn MC, Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 1997;385:347-50.[CrossRef][Medline]
64 Godden-Kent D, Talbot SJ, Boshoff C, Chang Y, Moore PS, Weiss RA, et al. The cyclin encoded by Kaposi's sarcoma associated herpesvirus (KSHV) stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. J Virol 1997;71:4193-8.[Abstract]
65 Li M, Lee H, Yoon DW, Albrecht JC, Fleckenstein B, Neipel F, et al. Kaposi's sarcoma-associated herpesvirus encodes a functional cyclin. J Virol 1997;71:1984-91.[Abstract]
66 Nicholas J, Ruvolo VR, Burns WH, Sandford G, Wan X, Ciufo D, et al. Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. Nat Med 1997;3:287-92.[CrossRef][Web of Science][Medline]
67 Neipel F, Albrecht JC, Ensser A, Huang YQ, Li JJ, Friedman KA, et al. Human herpesvirus 8 encodes a homolog of interleukin-6. J Virol 1997;71:839-42.[Abstract]
68
Molden J, Chang Y, Yow Y, Moore PS,
Goldsmith MA. A Kaposi's sarcoma-associated
herpesvirus-encoded cytokine homolog (vIL-6) activates signaling
through the shared gp130 receptor subunit. J Biol Chem 1997;272:19625-31.
69
Schwarze MM, Hawley RG. Prevention
of myeloma cell apoptosis by ectopic bcl-2 expression or
interleukin 6-mediated up-regulation of bcl-xL. Cancer Res 1995;55:2262-5.
70 Sarid R, Sato T, Bohenzky RA, Russo JJ, Chang Y. Kaposi's sarcoma-associated herpesvirus encodes a functional Bcl-2 homologue. Nat Med 1997;3:293-8.[CrossRef][Web of Science][Medline]
71
Cheng EH, Nicholas J, Bellows DS,
Hayward GS, Guo HG, Reitz MS, et al. A Bcl-2 homolog encoded by
Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits
apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci U S A 1997;94:690-4.
72 Thome M, Schneider P, Hofman K, Fickenscher H, Meinl E, Neipel F, et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 1997;386:517-21.[CrossRef][Medline]
73 Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS. KSHV ORF K9 (vIRF) is an oncogene that inhibits the interferon signaling pathway. Oncogene 1997;15:1979-86.[CrossRef][Web of Science][Medline]
74 Taniguchi T, Harada H, Lamphier M. Regulation of the interferon system and cell growth by the IRF transcription factors. J Cancer Res Clin Oncol 1995;121:516-20.[CrossRef][Web of Science][Medline]
75
Schindler C, Fu XY, Improta T,
Aebersold R, Darnell JJ. Proteins of transcription factor ISGF-3:
one gene encodes the 91-and 84-kDa ISGF-3 proteins that are
activated by interferon alpha. Proc Natl Acad Sci U S A 1992;89:7836-9.
76 Schindler C. Cytokine signal transduction. Receptor 1995;5:51-62.[Web of Science][Medline]
77
Weisz A, Kirchhoff S, Levi BZ. IFN
consensus sequence binding protein (ICSBP) is a conditional
repressor of IFN inducible promoters. Inter Immunol 1994;6:1125-31.
78 Maudsley DJ, Pound JD. Modulation of MHC antigen expression by viruses and oncogenes. Immunol Today 1991;12:429-31.[CrossRef][Web of Science][Medline]
79
Hobeika AC, Subramaniam PS, Johnson
HM. IFN
induces the expression of the cyclin-dependent
kinase inhibitor p21 in human prostate cancer cells. Oncogene 1997;14:1165-70.[CrossRef][Web of Science][Medline]
80 Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/ClP1 mediated by STAT1. Science 1996;272:719-22.[Abstract]
81 Sangfelt O, Erickson S, Einhorn S, Crander D. Induction of Cip/Kip and Ink4 cyclin dependent kinase inhibitors by interferon-alpha in hematopoietic cell lines. Oncogene 1997;14:415-23.[CrossRef][Web of Science][Medline]
82 Tanaka N, Ishihara M, Lamphier MS, Nozawa H, Matsuyama T, Mak TW, et al. Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. Nature 1996;382:816-8.[CrossRef][Medline]
83 Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, Ishihara M, et al. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 1993;259:971-4.[Abstract]
84
Reich N, Pine R, Levy D, Darnell
JJ. Transcription of interferon-stimulated genes is induced by
adenovirus particles but is suppressed by E1A gene products. J Virol 1988;62:114-9.
85 Bhattacharya S, Eckner R, Grossman S, Oldread E, Arany Z, D'Andrea A, et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Nature 1996;383:344-7.[CrossRef][Medline]
86
Cesarman E, Chang Y, Moore PS, Said
JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like
DNA sequences are present in AIDS-related body cavity based
lymphomas. N Engl J Med 1995;332:1186-91.
87 Rabkin CS, Bedi G, Musaba E, Sunkutu R, Mwansa N, Sidransky D, et al. AIDS-related Kaposi's sarcoma is a clonal neoplasm. Clin Cancer Res 1995;1:257-60.[Abstract]
88
Rabkin CS, Janz S, Lash A, Coleman
AE, Musaba F, Liotta L, et al. Monoclonal origin of multicentric
Kaposi's sarcoma lesions. N Engl J Med 1997;336:988-93.
89 Diaz-Cano SJ, Wolfe HJ. Clonality in Kaposi's sarcoma. N Engl J Med 1997;337:571.
90
Gill P, Tsai Y, Rao AP, Jones P.
Clonality in Kaposi's sarcoma. N Engl J Med 1997;337:570-1.
91
Soulier J, Grollet L, Oskenhendler
E, Cacoub P, Cazals-Hatem D, Babinet P, et al. Kaposi's
sarcoma-associated herpesvirus-like DNA sequences in multicentric
Castleman's disease. Blood 1995;86:1276-80.
92 Parravicini C, Corbellino M, Paulli M, Magrini U, Lazzarino M, Moore PS, et al. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV seronegative Castleman's disease. Am J Pathol. In press.
93
Holmberg S, Buchbinder S, Conley L,
Wong L, Katz M, Penley K, et al. The spectrum of medical
conditions and symptoms before acquired immunodeficiency syndrome
in homosexual and bisexual men infected with the human
immunodeficiency virus. Am J Epidemiol 1995;141:395-404.
94
Boshoff C, Endo Y, Collins PD,
Takeuchi Y, Reeves JD, Schweickart VL, et al. Angiogenic and
HIV-inhibitory functions of KSHV-encoded chemokines. Science 1997;278:290-4.
95 Baer R, Bankier AT, Biggin PL, Deininger PL, Farrell PJ, Gibson TJ, et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 1984;310:207-11.[CrossRef][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Bower, O. Veraitch, R. Szydlo, P. Charles, P. Kelleher, B. Gazzard, M. Nelson, and J. Stebbing Cytokine changes during rituximab therapy in HIV-associated multicentric Castleman disease Blood, May 7, 2009; 113(19): 4521 - 4524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lan, D. A. Kuppers, S. C. Verma, and E. S. Robertson Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Inhibits Lytic Replication by Targeting Rta: a Potential Mechanism for Virus-Mediated Control of Latency J. Virol., June 15, 2004; 78(12): 6585 - 6594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Jeong, J. Papin, and D. Dittmer Differential Regulation of the Overlapping Kaposi's Sarcoma-Associated Herpesvirus vGCR (orf74) and LANA (orf73) Promoters J. Virol., February 15, 2001; 75(4): 1798 - 1807. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||