Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy.
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ABSTRACT:
SUBMITTER: Dittmer DP
PROVIDER: S-EPMC5004954 | biostudies-literature | 2016 Sep
REPOSITORIES: biostudies-literature
Publications
Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy.
Dittmer Dirk P DP Damania Blossom B
The Journal of clinical investigation 20160901 9
Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogen ...[more]
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Project description:PURPOSE OF REVIEW:This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases. RECENT FINDINGS:KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV inflammatory cytokine syndrome (KICS) is a newly described syndrome with high mortality that has inflammatory symptoms-like MCD but not the pathologic lymph node findings. KSHV-associated diseases are often associated with dysregulated human interleukin-6, and KSHV encodes a viral interleukin-6, both of which contribute to disease pathogenesis. Treatment of HIV is important in HIV-infected patients. Strategies to prevent KSHV infection may reduce the incidence of these tumors. Pomalidomide, an immunomodulatory agent, has activity in Kaposi sarcoma. Rituximab is active in KSHV-MCD but can cause Kaposi sarcoma exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent Kaposi sarcoma. SUMMARY:KSHV is the etiological agents of all forms of Kaposi sarcoma and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition, and targeting of KSHV-infected cells are areas of active research.
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Project description:Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.
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Project description:A newly recognized gamma herpesvirus known as Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is present in Kaposi sarcomas and body-cavity-based lymphomas. Here we identify a novel abundant 1.2-kb RNA, polyadenylated nuclear RNA (PAN RNA), encoded by the virus. The majority of cDNAs produced from poly(A)-selected RNA isolated from a human body cavity lymphoma cell line 48 hr after butyrate induction of KSHV lytic replication represented PAN RNA. Within PAN RNA were two 9 and 16 nt stretches with 89% and 94% identity to U1 RNA. A third stretch of 14 nt was 93% complementary to U1. The 5' upstream region of PAN RNA contained both proximal and distal sequence elements characteristic of regulatory regions of U snRNAs, whereas the 3' end was polyadenylylated. PAN RNA was transcribed by RNA polymerase II, lacked a trimethylguanosine cap, and did not associate with polyribosomes. PAN RNA formed a speckled pattern in the nucleus typical of U snRNAs and colocalized with Sm protein. Therefore, PAN represents a new type of RNA, possessing features of both U snRNA and mRNA.
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Project description:BackgroundEndemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria coinfections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a cofactor in eBL pathogenesis.MethodsMultiplexed seroprofiles for EBV, malaria, and KSHV were generated for 266 eBL patients, 78 non-eBL cancers, and 202 healthy children. KSHV and EBV loads were quantified by PCR.ResultsKSHV seroprevalence did not differ by study group but was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with antimalarial antibody levels to AMA1 (odds ratio [OR], 2.41, P < .001; OR, 2.07, P < .001) and MSP1 (OR, 2.41, P = .0006; OR, 5.78, P < .001), respectively. KSHV loads did not correlate with antibody levels nor differ across groups but were significantly lower in children with detectable EBV viremia (P = .014).ConclusionsAlthough KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa.
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Project description:Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a rare, polyclonal lymphoproliferative disorder characterized by flares of inflammatory symptoms, edema, cytopenias, lymphadenopathy, and splenomegaly. Diagnosis requires a lymph node biopsy. Pathogenesis is related to dysregulated inflammatory cytokines, including human and viral interleukin-6. Rituximab alone or in combination with chemotherapy, such as liposomal doxorubicin, has led to an overall survival of over 90% at 5 years. Experimental approaches to treatment include virus activated cytotoxic therapy with high-dose zidovudine and valganciclovir and targeting human interleukin-6 activity. Despite successful treatment of KSHV-MCD, patients remain at high risk for developing non-Hodgkin lymphomas.
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Project description:Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies of endothelial and B-cell origin. The fact that latently infected tumor cells in these malignancies do not express classical viral oncogenes suggests that pathogenesis of KSHV-associated disease results from multistep processes that, in addition to constitutive viral gene expression, may require accumulation of cellular alterations. Heritable changes of the epigenome have emerged as an important co-factor that contributes to the pathogenesis of many non-viral cancers. Since KSHV encodes a number of factors that directly or indirectly manipulate host cell chromatin, it is an intriguing possibility that epigenetic reprogramming also contributes to the pathogenesis of KSHV-associated tumors. The fact that heritable histone modifications have also been shown to regulate viral gene expression programs in KSHV-infected tumor cells underlines the importance of epigenetic control during latency and tumorigenesis. We here review what is presently known about the role of epigenetic regulation of viral and host chromatin in KSHV infection and discuss how viral manipulation of these processes may contribute to the development of KSHV-associated disease.
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Project description:Purpose of reviewThe discovery of Kaposi sarcoma herpesvirus (KSHV) led to recognition of KSHV-associated multicentric Castleman disease (MCD) as a distinct lymphoproliferative disorder. The pathogenesis of KSHV-MCD is attributed to proliferation of KSHV-infected B cells, production of KSHV-encoded viral interleukin 6 by these cells, and dysregulation of human interleukin 6 and interleukin 10. This article reviews advances in the field of disease pathogenesis and targeted therapies.Recent findingsOur understanding of the pathogenesis of KSHV-MCD has increased in recent years and improved therapies have been developed. Recent studies demonstrate that the anti-CD20 monoclonal antibody, rituximab, as well as virus-activated cytotoxic therapy using high-dose zidovudine and valganciclovir, can control symptoms and decrease adenopathy. With treatment, 1-year survival now exceeds 85%. Interestingly, even in the absence of pathologic findings of MCD, KSHV-infected patients may have inflammatory symptoms, excess cytokine production, and elevated KSHV viral load similar to KSHV-associated MCD. The term KSHV-associated inflammatory cytokine syndrome has been proposed to describe such patients.SummaryRecent advances in targeted therapy have improved outcomes in KSHV-MCD, and decreased need for cytotoxic chemotherapy. Improved understanding of the pathogenesis of KSHV-MCD and KSHV-associated inflammatory cytokine syndrome is needed, and will likely lead to additional advances in therapy for these disorders.
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