Gammaherpesviruses and Lymphoproliferative Disorders

PM09CH15-Cesarman ARI 1 October 2013 14:35

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Gammaherpesvirusesand LymphoproliferativeDisordersEthel CesarmanDepartment of Pathology and Laboratory Medicine, Weill Cornell Medical College,New York, NY 10065; email: [email protected]

Annu. Rev. Pathol. Mech. Dis. 2014. 9:349–72

The Annual Review of Pathology: Mechanisms ofDisease is online at pathol.annualreviews.org

This article’s doi:10.1146/annurev-pathol-012513-104656

Copyright c© 2014 by Annual Reviews.All rights reserved

Keywords

Kaposi’s sarcoma herpesvirus, KSHV, Epstein–Barr virus, EBV,human herpesvirus 8, HHV-8, cancer, lymphoma, multicentricCastleman’s disease, acquired immunodeficiency syndrome, AIDS,human immunodeficiency virus, HIV

Abstract

Epstein–Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV),formally designated human herpesvirus 4 (HHV-4) and 8 (HHV-8),respectively, are viruses that can cause a variety of cancers in humans.EBV is found in non-Hodgkin and Hodgkin lymphomas, as well asin lymphoproliferative disorders, which occur more commonly butnot exclusively in individuals with immunodeficiency. EBV also causesnonlymphoid malignancies such as nasopharyngeal carcinoma. KSHVcauses primary effusion lymphomas, multicentric Castleman’s disease,and Kaposi’s sarcoma. The frequency of lymphoid malignancies relatedto infection by one of these two herpesviruses is greatly increased inindividuals with immunodeficiency, whether primary or acquired, forexample, as a consequence of HIV infection and AIDS or in the caseof therapeutic immunosuppression for organ transplantation. Ourcurrent understanding indicates that EBV and KSHV contribute tolymphomagenesis by affecting genomic stability and by subvertingthe cellular molecular signaling machinery and metabolism to avoidimmune surveillance and enhance tumor cell growth and survival.Understanding the viral associations in specific lymphoproliferative dis-orders and the molecular mechanisms of viral oncogenesis will lead tobetter prevention, diagnosis, and treatment strategies for these diseases.

349

Review in Advance first posted online on September 9, 2013. (Changes may still occur before final publication online and in print.)

Changes may still occur before final publication online and in print

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INTRODUCTION

Individuals with immunodeficiency have agreatly increased risk of developing cancer.This risk appears to be due primarily to a lossof immune surveillance to tumor antigens,in combination with other factors such asincreased inflammation and infectious agents.Among tumor antigens are proteins expressedby oncogenic viruses. The vast majority ofindividuals are infected by the Epstein–Barrvirus [EBV; formally designated as human her-pesvirus 4 (HHV-4)] without any pathogenesis,but EBV-associated lymphoid malignanciesemerge as a leading cause of cancer in peoplewith immunodeficiency. Similarly, Kaposi’ssarcoma herpesvirus [KSHV; also known as hu-man herpesvirus 8 (HHV-8)] commonly causescancer in people with HIV infection but onlyrarely in immunocompetent individuals. Bothof these viruses belong to the gamma subfamilyof the human herpesviruses, and both caninfect B lymphocytes. Like all other membersof the herpesvirus family, they can establish alatent infection in which infectious virions arenot produced and only a limited number ofviral transcripts and proteins are synthesized.During latent infection, both EBV and KSHVexpress proteins and noncoding RNAs thataffect the cell cycle, promote cellular prolifer-ation, and inhibit apoptosis. These effects arebelieved to be necessary for the viruses to sur-vive in the appropriate cellular reservoir as partof their normal life cycle. In healthy individu-als, the immune system limits this proliferationbecause it recognizes some of the potentiallyoncogenic viral proteins. If this process failsbecause of abnormal immune responses, viralpromotion of cellular proliferation can gounchecked, leading to a malignancy. Infectionof B cells by EBV and KSHV can thus lead tothe development of a variety of lymphoprolif-erative disorders (LPDs), which are illustratedin Figure 1 and reviewed in the followingsections.

LPDs ASSOCIATED WITHEBV INFECTION

Burkitt Lymphoma

The description of Burkitt lymphoma (BL) hasbeen attributed to Dennis Burkitt, who in 1958described this unique tumor involving the jawin African children (1). However, the first de-scription was much earlier: Albert Cook, thefirst missionary doctor in Uganda, who arrivedthere in 1896, reported a child with a large jawtumor that was most likely a BL (2). Follow-ing Burkitt’s description, EBV was discoveredand isolated from BL tumors (3) and identi-fied as the causal agent of infectious mononu-cleosis (4). We now know that there are threeepidemiologic subtypes of BL: endemic, spo-radic, and HIV associated. The endemic type,described in Africa, presents as an abdominalor jaw mass in children in equatorial Africa andPapua New Guinea, regions where malaria isendemic. Most of these cases are EBV posi-tive; that is, the viral genome and transcriptscan be found in every tumor cell. The sporadictype, found in the United States and Europe,most often presents in lymph nodes and is as-sociated with EBV in approximately 20% ofcases. HIV-associated BL is found worldwideand is associated with EBV in approximately30% of cases. All three epidemiologic subtypeshave in common the translocation of the MYCproto-oncogene to one of three immunoglob-ulin chains, which leads to deregulated expres-sion of the MYC protein.

BLs are characterized histologically by thepresence of sheets of medium-sized monomor-phic cells with round nuclei and basophiliccytoplasm (Figure 2). Infiltrating macrophagesthat have ingested apoptotic tumor cells give aclassic starry-sky appearance. BL cells expresscommon B cell antigens (CD19, CD20, CD22,CD79a, PAX5). Expression of the germinal-center B cell–specific markers (CD10, BCL6)and lack of BCL2 are characteristic of BL,and immunohistochemistry for these threeantibodies is helpful to distinguish BL from

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AIDS Iatrogenicimmunosuppression:organ transplantation

autoimmunity

Congenitalimmunodeficiency

LymphomaKaposi’ssarcoma

Atypical lymphoproliferative disorders(PH and PBCH)

KSHV EBV

100%100% 100%100%

>90%>90%

~40%40% ~30%30%

>80%>80%

100%100%100%100%

>90%>90%100% 100%

>90%

~40% ~30%

>80%

100%

MCD

100%

DLBCLPEL BL PBL HL

>90%

Figure 1Infection with Epstein–Barr virus (EBV) or Kaposi’s sarcoma herpesvirus (KSHV) in malignancies occurringin patients with immunodeficiency. The major subtypes of lymphoproliferative disorders are shown in boxes,with arrows indicating the cause of immunodeficiency and the most common associations. Percentage ofEBV infection is an approximation based on a compilation of the literature and the author’s personalexperience, and reflects only the proportion of cases that occur in the context of HIV infection; thesenumbers are much lower for multicentric Castleman’s disease (MCD), diffuse large B cell lymphoma(DLBCL), and Hodgkin lymphoma (HL) in individuals without overt immunodeficiencies. Additionalabbreviations: BL, Burkitt lymphoma; PBCH, polymorphic B cell hyperplasia; PBL, plasmablasticlymphoma; PEL, primary effusion lymphoma; PH, plasmacytic hyperplasia. Modified with permission fromReference 164.

other lymphomas when the morphologyis atypical. BL is among the most rapidlygrowing tumors, which can be appreciatedhistologically by numerous mitotic figures andby immunohistochemistry for Ki67, which ispositive in nearly 100% of the cells.

Nearly all BLs contain a translocation ofthe MYC locus, located in 8q24 (Figure 3).The most common partner is immunoglobulinheavy chain (IgH), on chromosome 14q32, butrearrangements with the κ (22q11) or λ (2p12)light chains are also observed. The method ofchoice to demonstrate this translocation is fluo-rescent in situ hybridization (FISH) (Figure 3).Deregulated MYC expression is thought tobe a central driving force in the pathogenesisof BL. MYC is a nuclear phosphoproteinwith gene-activating and gene-repressingcapabilities that is involved in many cellular

processes, including growth (increase in cellsize), proliferation (DNA replication and cellcycle control), and metabolism (5). In additionto MYC translocation, other cellular geneticalterations have been reported. Loss of thetumor-suppressor gene TP53 is common inthese tumors, and recent next-generationsequencing studies have revealed previouslyunknown molecular alterations (5–8). Themost frequent, after MYC translocation, appearto be mutations in the TCF3 (also known asE2A) gene or its negative regulator ID3, whichtogether can be found in up to 70% of sporadicand AIDS-related BLs and in approximately40% of endemic BLs (8). Alterations in thispathway lead to tonic B cell receptor signalingand activation of the phosphoinositide 3-kinase(PI3K) pathway (8). Another commonly alteredgene is CCND3, encoding cyclin D3; this gene

www.annualreviews.org • Gammaherpesviruses and LPDs 351


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Posttransplantation lymphoproliferative disorders

AIDS-related lymphomas

Polymorphic DLBCLPH

DLBCL-IB HLBL

EBER LMP1H&E

Figure 2Histopathology of Epstein–Barr virus (EBV)-associated diseases. (Top row) Hematoxylin and eosin (H&E)-stained sections of tissuesinvolved by posttransplantation lymphoproliferative disorders are shown. These include examples of a plasmacytic hyperplasia (PH),showing a majority of mature reactive lymphocytes with some immunoblasts and plasma cells; a polymorphic lymphoproliferativedisorder, with a heterogeneous (polymorphic) cell population with atypical immunoblasts; and a diffuse large B cell lymphoma(DLBCL), or monomorphic posttransplantation lymphoproliferative disorder, showing sheets of large neoplastic cells. Originalmagnification 60× . (Middle row) Examples of AIDS-related lymphomas, including a Burkitt lymphoma (BL) with sheets ofmedium-sized cells and a starry-sky pattern due to macrophages with necrotic debris and mitotic figures; a DLBCL with immunoblastic(IB) features (large atypical cells that have an eccentric nucleus, with a central prominent nucleolus, and abundant cytoplasm); and aHodgkin lymphoma (HL) with a classic Reed–Sternberg cell. Original magnification 60× . (Bottom row) EBV-positive AIDS-relatedlymphoma. H&E staining shows diffuse infiltration of neoplastic lymphocytes; in situ hybridization for EBV-encoded RNA (EBER)shows dark-purple positivity in the majority of the nuclei; and immunohistochemistry for LMP1 (latent membrane protein 1) showscytoplasmic positivity (brown) in many of the tumor cells. Original magnification 100× . Modified with permission from Reference 165.

is altered in approximately one-third of cases.Mutations in this gene lead to a more stablecyclin D3 protein that may enhance cell cycleprogression. Additional recurrent alterations

include truncating mutations in ARID1A, amember of the SWI/SNF family of chromatinremodeling complexes that has been impli-cated as a tumor suppressor, and copy-number

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MYC

IgH

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y

ba

Figure 3MYC translocations in Burkitt lymphoma. (a) Metaphase spread showing a conventional t(8;15) (q24;q32)chromosomal translocation. (b) Cytogenetic analysis of a case of Burkitt lymphoma shows a metaphasespread done on an EBV-positive cell line, with fluorescent in situ hybridization showing a balancedtranslocation involving the MYC and IgH loci. The chromosome 8 centromere is labeled with spectrumaqua, the MYC probe is labeled in spectrum orange, and the IgH probe is labeled with spectrum green. Twofusion signals are seen, as well as one red and one green, which represent the normal chromosomes. Imagescourtesy of Dr. Susan Mathew.

gains in MCL1, which lead to overexpressionof the antiapoptotic MCL1 protein in BL(5). Cases that lack EBV are more likely thancases with EBV to have multiple mutations,consistent with a tumorigenic role of EBV ina subset of BL (5).

Diffuse Large B Cell Lymphomas

Diffuse large B cell lymphoma (DLBCL) is arelatively common lymphoma subtype in thegeneral population, but it is markedly increasedin individuals with AIDS. EBV is present inapproximately one-third of DLBCL cases inindividuals with immunodeficiency and is alsocommon in DLBCL cases in older people. Inthe context of AIDS, DLBCL can be dividedinto centroblastic (CB) and immunoblastic (IB)histologic categories (Figure 2). EBV is morecommon in the IB subtype; reported rates ap-proach 90%. Patients with the IB variant usuallyhave advanced AIDS and are significantly im-munosuppressed, so the frequency of this sub-type has greatly decreased with the widespreaduse of antiretroviral therapy in the UnitedStates and Europe. Primary central nervous sys-tem (CNS) lymphoma is similar to the IB vari-

ant in that it has an immunoblastic morphology,frequently involves EBV infection, and hasbeen decreasing in frequency. CB DLBCL inHIV-positive patients is similar to DLBCL inimmunocompetent individuals, except that theformer is more frequently associated with EBV(30% of cases) than is the latter (<5% of cases).These categories can be similarly divided intogerminal-center and non-germinal-centersubtypes, although the clinical significance ofthis subclassification remains controversial andmay be treatment dependent (9–11). Manylarge genomic studies have focused on DL-BCL; these studies have identified numerousgenetic alterations, some of which correlatewith tumor subtype (recently reviewed in 12).However, few have addressed the relationshipbetween EBV infection and specific geneticalterations. One study showed that mutationsand deletions of TNFAIP3 that lead to the lossof A20 protein (formally designated TNAP3)expression can be found in both EBV-positiveand EBV-negative cases of AIDS-related lym-phoma. In most cases with A20 loss, the EBVlatent membrane protein 1 (LMP1) was notexpressed. Because both A20 loss and LMP1lead to nuclear factor κB (NF-κB) activation,



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this finding suggested that loss of A20 may bean alternative mechanism of NF-κB activationin the absence of LMP1 expression (13).

B Cell Lymphoma, Unclassifiable,with Features Intermediate BetweenDiffuse Large B Cell Lymphoma andBurkitt Lymphoma

Some aggressive lymphomas do not fit cleanlyinto the DLBCL or BL categories, so the WHOclassification of hematologic malignancies hasnow placed them into an “unclassifiable” cate-gory (15). These cases were previously knownas Burkitt-like or atypical Burkitt lymphoma.To fall under this classification, cases must havean unusual morphology, an unusual phenotype,or both. The presence of MYC translocationsin an otherwise typical DLBCL or the lackof MYC alterations in a typical BL is not suf-ficient for this diagnosis. The designation “Bcell lymphoma, unclassifiable, with features in-termediate between DLBCL and BL” appearsto be a heterogeneous category that is usefulonly for classification purposes and may serveas a placeholder until this category is better un-derstood. Some of these cases may belong toa distinct molecular category characterized bya MYC translocation plus a complex karyotypeand/or may correspond to those cases that areinitially classified as BL but upon gene expres-sion profiling do not have a Burkitt signature(16, 17). Both EBV-positive and EBV-negativecases can be found in this category.

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is characterized his-tologically by complete or partial effacementof the lymph node architecture along with rareReed–Sternberg cells, which are large and of-ten binucleated cells with prominent nucleoli(Figure 2). These are scattered among a reac-tive cell infiltrate composed of variable propor-tions of lymphocytes, histiocytes, eosinophils,and plasma cells. Reed–Sternberg cells are ofB cell origin, although they do not express Bcell antigens, and they have a CD45−, CD30+,

CD15+ immunophenotype. Mononuclear vari-ants of Reed–Sternberg cells are also found;these have been termed Hodgkin cells. EBVmay be present in these Reed–Sternberg cellsand variants in a subset of cases.

There are several subtypes of classical HL.Nodular sclerosis, which occurs in at least one-half of cases, is the most common in the gen-eral population, followed by the mixed cellu-larity subtype, which occurs in approximatelyone-quarter of cases. The other two subtypesare lymphocytic depletion and lymphocyte rich.This distribution is different in developingcountries and in minority populations of lowersocioeconomic status within the United States,in which the most common histologic subtypesare mixed cellularity and lymphocytic depletion(18); these are the subtypes more commonly as-sociated with EBV.

Although HL is not considered an AIDS-defining condition, HL risk is increased inHIV-infected individuals, and this disease ap-pears to have become more common in the eraof combined antiretroviral therapy. It has beenhypothesized that this is a consequence of pa-tients surviving longer and having higher CD4counts, which may be necessary for this diseaseto develop (19). Approximately one-third of allHLs in immunocompetent individuals are pos-itive for EBV, but this proportion is higher indeveloping countries and in immunodeficientpatients. In the context of HIV, the vast major-ity of cases are associated with EBV infection(20, 21).

Plasmablastic Lymphoma

Plasmablastic lymphoma (PBL) is a high-grade,aggressive lymphoid malignancy that was firstreported in the oral cavity of HIV-infected in-dividuals but later was shown to also occur inother sites and in conjunction with other im-munodeficient states. The vast majority of casesin the oral cavity are associated with EBV, andthis virus is present in approximately 75% ofcases occurring at other sites. The immunophe-notype is that of plasma cells, with expressionof monotypic cytoplasmic immunoglobulin in

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most cases. The criteria used for classificationof PBL have evolved over time. Some reportsuse a very strict definition that includes presen-tation in the oral cavity and presence of EBV;if these criteria are used, PBLs are extremelyrare (22). Others use a broader definition, suchas that provided by the WHO, which acceptsEBV-negative cases and extraoral presentationas long as the morphology and immunopheno-type is that of B immunoblasts or plasma cells(23).

PosttransplantationLymphoproliferative Disorder

Posttransplantation lymphoproliferative disor-der (PTLD) is an EBV-associated disease thatdevelops in the setting of immunosuppres-sion following solid organ transplantation orallogeneic bone marrow transplantation. Therelative incidence of these lesions is higher inpatients who are EBV negative at the time oftransplantation and who do not have underlyingimmunity to the virus (24). Studies of PTLDsoccurring in solid organ transplantation recip-ients have led to three classification categoriesbased on morphologic and molecular geneticcriteria (24–26): (a) plasmacytic hyperplasia(PH) and infectious mononucleosis (IM)-likePTLDs, which retain the overall architectureof the tissue, are more common in childrenthan adults and are typically polyclonal basedon Ig rearrangement studies; (b) polymorphicPTLDs, which are monoclonal lesions thatshow destruction of the underlying architectureand are composed of a heterogeneous (poly-morphic) cell population; and (c) monomorphicPTLDs, in which lesions are composed ofcytologically malignant monoclonal cells andshould be classified according to standardlymphoma classification criteria. PTLDs fromall three categories are most frequently of Bcell origin; the monomorphic cases usuallyfit the classification for DLBCL but, less fre-quently, can be BLs or plasma cell neoplasmssuch as multiple myeloma or plasmacytoma.Cytogenetic abnormalities are common inthe monomorphic lesions, and they contain

structural alterations in oncogenes and tumor-suppressor genes frequently involved in lym-phomagenesis such as TP53, N-RAS, and MYC(26, 27). Although the majority of PTLDs areassociated with EBV infection, the proportionof EBV-negative cases increases with time afterorgan transplantation, and most EBV-negativecases belong to the monomorphic category (28).

EBV-Associated T Cell and NaturalKiller Cell Malignancies

Although EBV is most frequently found in lym-phomas of B cell origin, it is also present in somenon–B cell cancers. EBV is found in most casesof aggressive natural killer (NK) cell leukemia,a rare disease most prevalent in Asia (29). Extra-nodal NK-T cell lymphoma, nasal type, is an-other malignancy clearly associated with EBV.Other names for this cancer type are angiocen-tric T cell lymphoma and lethal midline granu-loma. This disease is characterized by vasculardamage, necrosis, and a cytotoxic T cell pheno-type; it occurs most frequently in the upper res-piratory tract but can also present in other ex-tranodal and nodal sites. Its incidence is higherin Asians and Native Latin Americans (30).Two different T cell LPDs in children havebeen reported with EBV infection: (a) systemicEBV-positive LPD of childhood, characterizedby proliferation of EBV-infected activated cy-totoxic T cells; and (b) hydroa vacciniforme–likelymphoma, an EBV-positive cutaneous T celllymphoma associated with sun sensitivity (31).

LPDs Associated with PrimaryImmunodeficiency

Children and adults with many forms ofprimary immunodeficiency (PID) have anincreased risk of developing LPDs, some ofwhich are specifically associated with EBV.These may arise because of a lack of immuno-logical control of EBV-driven B cell expansionsor as consequence of immunological dysreg-ulation and lymphoid hyperactivation. Morethan 175 different PIDs are now recognized,so each specific entity is quite rare (32). Several



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previously described syndromes have beensubdivided into individual disease entities as thegenetic defects have been elucidated. Both theclinical presentation and the specific immuno-logical defects are highly heterogeneous, andprecise diagnosis can be challenging, with theexception of some very well defined syndromes.This diagnosis relies on careful assessment ofcirculating lymphoid subpopulations and ofantibody classes produced and, increasingly,on molecular studies of affected families.

Individuals affected by PIDs are susceptibleto recurrent infections and/or autoimmunity.In addition, children and adults with PID havean overall risk for developing malignancies of4% to 25% (33–35)—cancer is the second mostcommon cause of death. Lymphoma is the mostcommon malignancy, representing nearly 60%of all cancers in patients with PID, who havean 8-fold increased risk over the general pop-ulation (34, 36); of these, approximately 50%are non-Hodgkin lymphoma (NHL) and nearly8% are HL.

Much of our understanding of the specificPIDs that are associated with LPD comes fromlarge registries (with limited pathologic anal-ysis), small series, or case reports. Accord-ing to the Immunodeficiency Cancer Registrydata, more than 80% of cancers in individ-uals with PID are in patients with one ofthe following syndromes: ataxia telangiecta-sia (30%), common variable immunodeficiency(24%), Wiskott-Aldrich syndrome (16%), se-vere combined immunodeficiency (8%), andselective IgA deficiency (8%) (35). Less com-mon PIDs, such as X-linked lymphoprolifer-ative disorder and autoimmune lymphoprolif-erative syndrome, are notable for their strongassociation with LPD (34, 36, 37).

Primary Effusion Lymphoma

Approximately 90% of primary effusion lym-phomas (PELs) contain both EBV and KSHV.Because KSHV is a defining feature of this dis-ease, it is described below in the section aboutKSHV-associated lymphoid proliferations.

Mechanisms of EBV-MediatedLymphomagenesis

Like other herpsesviruses, EBV can be in one oftwo stages. Lytic infection is when the virus pro-duces a large number of functional and struc-tural proteins to replicate its DNA and produceinfectious viral particles, usually leading to de-struction of the host cell. In contrast, duringlatency, only a limited number of viral proteinsare made. Although the pattern of EBV geneexpression can be heterogeneous, a simplifiedclassification establishing three patterns of la-tency has been used (Figure 4) (38). In latencyI, EBV nuclear antigen (EBNA) 1 is the majorviral protein expressed. EBNA1 is necessary fortethering the viral DNA to the dividing host cellchromosomes, thereby maintaining the episo-mal EBV. This latency pattern is established ininfected memory B cells in long-term infectionin healthy individuals. On the other end of thespectrum, latency III involves the unrestrictedexpression of all nine latent genes, includingsix EBV-encoded nuclear antigens (EBNA1–6) and three latent membrane proteins (LMP1,LMP2A, and LMP2B). These viral proteins arehighly immunogenic, so this latency usually oc-curs in severely immunodeficient individuals. Inaddition, this is the latency seen in lymphoblas-toid cell lines, which are B cells immortalizedby EBV infection in vitro. Latency II is an inter-mediate pattern, with expression of EBNA1 andother latent proteins, but without expression ofone of the two critical EBV transforming pro-teins (EBNA2 in type IIa latency and LMP1in type IIb) (39). Recently, a different latencypattern, termed Wp-restricted latency, was re-ported in BL in vivo; approximately 15% of BLshave mutant EBV genomes with deletions thatinclude EBNA2 and use the Wp promoter (usu-ally not used in BL), leading to expression ofEBNA3A–C proteins, in addition to EBNA1,in the absence of EBNA2 and the LMPs (40).BL cells that have these deleted versions of EBVhave a higher resistance to apoptosis, which isdue to expression of a viral BCL2 homolog,BHRF1, that is normally a lytic gene (41).

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Latency I Latency II Latency III

EBV geneexpression profiles inlympho-proliferativediseases

Lymphoma type

EBER

LMP1

EBNA2

Burkitt(HIV +/–)

Primaryeffusion

Hodgkin NK-T cell AIDS-NHLDLBCL

Immunoblastic

PTLD

EBVtranscription

programs

LatencyNo viral gene

expression

EBNA1 only DefaultEBNA1, LMP1,

and LMP2A

GrowthEBNA1–6, LMP1,

LMP2A, and LMP2B

LyticAll lytic genes

Type of infected cell

Resting memoryB cell

Dividing memory B cell

Germinal-centerB cell

Naive B cell orbystander cell

Plasma cell

Figure 4Patterns of Epstein–Barr virus (EBV) latent gene expression in healthy individuals and in malignant lymphomas. The patterns ofEBV-infection gene expression described in different B cell subsets are shown in the upper table. Corresponding expression profiles inmalignant lymphomas have been designated latencies I, II, and III and are shown in the lower table. EBV-encoded RNA (EBER) in situhybridization is used to detect the presence of EBV; immunohistochemical positivity for latent membrane protein 1 (LMP1) denoteslatency II or III; and EBV nuclear antigen 2 (EBNA2) protein expression together with LMP1 positivity indicates latency III.Abbreviation: DLBCL, diffuse large B cell lymphoma; NHL, non-Hodgkin lymphoma; NK, natural killer; PTLD, posttransplantationlymphoproliferative disorder. Modified with permission from Reference 166.

In addition to these diverse viral pro-teins, EBV expresses several noncoding RNAs.Among these are the EBV-encoded RNA(EBER) 1 and 2, which are small noncodingRNAs expressed ubiquitously and abundantlyin EBV-infected cells; because of these features,they have become the basis for a useful diagnos-tic technique for EBV infection using in situhybridization (Figure 2). The function of theEBERs is not completely clear, but they havebeen reported to protect cells from apoptosis,

although they are not essential for transforma-tion or maintenance of a transformed pheno-type in vitro (42–44). EBERs can also upregu-late the amount of interleukin (IL)-10 mRNAin B cells (45), so they may play a role in tran-scriptional or posttranscriptional regulation ofthis and other genes.

MicroRNAs (miRs) are also expressed dur-ing EBV latency, and at least 22 precursor and44 mature EBV miRs have been identified (44,46). Which specific miRs are expressed appears



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to vary according to cell type and experimen-tal system. A cluster of miRs, encoded in theBamHI fragment H region of the genome andtherefore termed BHRF1 miRs, is not detectedin nasopharyngeal carcinoma (NPC) cells butis expressed in latency IIIb cells and at lowlevels in latency I cells (47, 48). The roles ofthese miRs are just beginning to be elucidated,but some interesting functions have startedto appear. For example, it has been recentlydemonstrated that the viral miRs in the BHRF1region inhibit apoptosis and favor cell cycleprogression and proliferation during the earlyphase of infection in human primary B cells(49).

Latency I is seen in BL; in some AIDS-related lymphomas (ARLs), including DL-BCL, PBL, and PEL; and in some monomor-phic PTLDs (50–52). In these, only EBNA1,EBERs, and several miRs are expressed, andother driving oncogenic alterations are present.EBNA1 is essential for viral genome mainte-nance (53). The role of EBNA1 in oncogen-esis has been debated, but it appears to havesome effects on cellular survival. An increasedincidence of lymphomas has been reported inEBNA1 transgenic mice (54), and infection ofB cells with EBNA1-deleted EBV leads to thedevelopment of LCLs with markedly reducedefficiency when compared with infection withwild-type EBV (55). Additional evidence thatEBNA1 can provide growth and survival ef-fects to BL cells in culture has emerged (56, 57).Lymphomas with latency I have cellular onco-genic alterations, such as translocations involv-ing the MYC oncogene characteristic of BLs(58–60), so it is likely that EBNA1 protectsfrom apoptosis in the context of deregulatedMYC expression. This protection from apo-ptosis would be further enhanced by expres-sion of the BCL2 homolog BHRF1 in caseswith Wp-restricted latency (41). Other types ofLPDs with type I EBV latency have additionaltransforming alterations. In PEL, the KSHVgenome produces several potentially oncogenicproteins, and in DLBCL, genetic alterationscan be found in BCL6, cMYC, BCL2, TP53,N-RAS, and TNFAIP3 (A20).

In tumors with less restricted latency pat-terns, namely types II and III, EBNA2 and/orLMP1 proteins are expressed. Both these pro-teins are essential for transformation by EBVin vitro. EBNA2 can activate the Notch sig-naling pathway (61, 62). The LMP1 proteinis transforming and tumorigenic in vitro (63)and in transgenic mouse models (64, 65). LMP1functions as a constitutively active tumor necro-sis factor receptor (TNFR) by aggregating inthe membrane as its cytoplasmic tail inter-acts with TNFR-associated factors (TRAFs)and TNFR1-associated death domain protein(TRADD), leading to activation of NF-κB andthe c-Jun amino-terminal kinase ( JNK) (66–68). In AIDS-related lymphomas, LMP2A alsocontributes to NF-κB signaling by enablingLMP1 signaling (69). Knockdown of eitherLMP1 or LMP2A with RNA interference re-sults in NF-κB downregulation and apoptosis,indicating that both are important for the sur-vival of type III lymphoma cells and are poten-tial therapeutic targets (69).

LPDs CAUSED BY KSHV

Primary Effusion Lymphoma

KSHV was first discovered as the causal agent ofKaposi’s sarcoma, but soon thereafter, this viruswas found in a distinct subtype of lymphoma,termed primary effusion lymphoma (PEL) (70,71). PEL occurs more frequently, but not ex-clusively, in HIV-infected individuals and ac-counts for approximately 4% of all HIV-relatedNHLs. These lymphomas frequently presentas an effusion involving one or more of thepleural, peritoneal, and pericardial spaces andlack expression of B cell–associated antigens,in spite of a B cell genotype. Although mostcases remain localized to body cavities as effu-sions (thus the designation of PEL), in approx-imately one-third of cases, dissemination to ex-tracavitary sites occurs. KSHV has also beenidentified in the tumor cells of some AIDS-related lymphomas with no evidence of bodycavity involvement. These represent approx-imately 5% of all AIDS-related NHLs; they

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Primary effusion lymphoma

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Figure 5Histopathology of Kaposi’s sarcoma herpesvirus (KSHV)-associated lymphoproliferative diseases. Primary effusion lymphoma:(a) Wright–Giemsa stain air-dried cytocentrifuge preparation of a KSHV-positive primary effusion lymphoma. The tumor cells in thisimage are considerably larger than normal benign lymphocytes and monocytes. The cells display significant polymorphism and possessmoderately abundant basophilic cytoplasm. A prominent, clear perinuclear Golgi zone can be appreciated in several cells. The nucleivary from large and round to highly irregular, multilobated, and pleomorphic and often contain one or more prominent nucleoli.Immunohistochemical staining with the following antibodies is shown: (b) LANA (ORF 73); a monoclonal rat antibody shows brownspeckled nuclear positivity in all the neoplastic cells. (c) vIL-6; a polyclonal rabbit antiserum shows abundant cytoplasmic expression(brown) in many lymphoma cells. Multicentric Castleman’s disease: (d ) Hematoxylin and eosin (H&E)-stained section of a lymph nodewith HIV-associated Castleman’s disease shows a single follicle with a large, concentrically arranged mantle zone surrounding agerminal center. The interfollicular area contains a network of small vessels. Immunohistochemical staining with the followingantibodies is shown: (e) LANA. ( f ) LANA and κ light chain double staining shows nuclear positivity (red ) in cells that are negative forcytoplasmic κ (brown). ( g) LANA and λ light chain double staining shows cells that are positive for nuclear LANA (red ) as well ascytoplasmic λ (brown). (h) K8.1; a monoclonal antibody shows cytoplasmic positivity (brown) in two cells that are undergoing lytic viralreplication. (i ) vIL-6; cytoplasmic staining using a rabbit polyclonal antiserum shows positivity in numerous cells in the mantle zone.Adapted from Reference 165.

have the morphology of large cell immunoblas-tic lymphoma, but like PELs, they frequentlylack expression of B cell antigens and are com-monly coinfected with EBV (72), so they havebeen termed extracavitary or solid variants ofPEL. Additional diagnostic criteria include animmunoblastic-anaplastic large cell morphol-

ogy (Figure 5), null-cell phenotype (includingthe lack of B cell–associated antigen and im-munoglobulin expression in most cases), andexpression of CD138/Syndecan-1. PELs haveimmunoglobulin gene rearrangements (70) andhypermutation of the immunoglobulin genes(73), indicating a post–germinal center stage of



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B cell differentiation. Gene expression profil-ing of PEL (74, 75) has revealed that tumorcells resemble plasma cells and have a tran-scriptional signature between those of multiplemyeloma and EBV-associated immunoblasticlymphoma.

Multicentric Castleman’s Disease

Castleman’s disease has been divided into twodistinct histopathologic subtypes: the morecommon hyaline vascular type and the plasmacell type (76). It has also been divided into clin-ical forms: localized and multicentric Castle-man’s disease (MCD). Most cases of MCD havethe plasma cell type morphology, but this sep-aration is not absolute. MCD is characterizedclinically by lymphadenopathy accompanied bysystemic symptomatology that includes fevers,malaise, wasting, hypoalbuminemia, cytope-nias, and hyponatremia (77). These patientsmay develop malignancies, most commonlyKaposi’s sarcoma and NHL. An associationof KSHV with MCD was reported soon afterthe discovery of this virus, which is present inapproximately one-half of MCD cases in im-munocompetent individuals and in almost allMCD cases in individuals with HIV (78). MCDis characterized by hyalinized atrophic follicles,expanded interfollicular areas, and prominentvascular proliferation, the latter of which maybe reminiscent of Kaposi’s sarcoma and hasled to an alternative designation of MCDas multicentric angiofollicular hyperplasia(Figure 5). Although KSHV has been reportedin MCD with both hyaline vascular and plasmacell morphology (79), most cases more closelyresemble the plasma cell type of MCD. Thesecases are now thought to represent a distinctentity with distinguishing histological features,including more angiosclerosis and germinal-center and perifollicular vascular proliferation,and plasmacytosis is less pronounced than inthe KSHV-negative cases of the plasma celltype (80). The presence of larger cells in themantle zones—which are termed plasmablastsand contain KSHV—defines KSHV-associatedMCD (81). This virus is detected in histo-

logical sections by immunohistochemistrywith monoclonal antibodies to the latentKSHV protein LANA (ORF 73) (Figure 5)(82). The infected cells can be numerous,coalesce, and form microlymphomas or franklymphomas (described below). KSHV-infectedplasmablasts are B cells that are monotypic butpolyclonal and express IgMλ (Figure 5) (83).

MCD appears to be a disorder of immunedysregulation, and the constitutional symptomsare thought to be due to production of excesscytokines; IL-6, which is markedly elevated inthis disease, is likely an important contributor.Notably, KSHV encodes a homolog of IL-6,termed viral IL-6 (vIL-6), which may be asso-ciated with MCD pathogenesis and contributeto the symptoms: It is produced by KSHV-infected plasmablasts (Figure 5) (84–86), andexpression of this viral cytokine has been re-ported to confer a worse prognosis (87). OtherKSHV lytic proteins (e.g., K8.1) can also befound in KSHV-associated MCD, which sug-gests that there is uncontrolled viral prolifera-tion in this disease (Figure 5). Furthermore, anIL-6-related systemic inflammatory syndromehas been reported in patients with HIV and Ka-posi’s sarcoma but without a pathologic diag-nosis of MCD (88), and high serum levels ofvIL-6 have been found in similar patients, fur-ther supporting the notion that at least someof the symptomatology of MCD is due to thisviral cytokine.

Lymphoma Arising inKSHV-Associated MulticentricCastleman’s Disease

A rare lymphoma type has been describedmainly in HIV-positive patients with MCD(81). It was initially designated as plasmablas-tic lymphoma, but because it differs from thePBL category in that the tumor cells containKSHV rather than EBV, an alternative descrip-tive nomenclature was adopted (21). These tu-mors differ from PEL in that (a) they are EBVnegative, (b) they do not contain mutations inthe immunoglobulin genes, and (c) they arethought to arise from naive IgMλ-expressing

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B cells rather than terminally differentiated Bcells. Another very rare KSHV-associated lym-phoma entity, termed germinotropic lympho-proliferative disorder, has also been described,in which germinal center B cells are coinfectedwith EBV and KSHV (89).

Mechanisms of KSHV-MediatedTumorigenesis

The presence of KSHV is considered a defin-ing feature of PEL. Although reports havedescribed patients presenting with a primarylymphomatous effusion that lacks KSHV, thisappears to be a different disease entity, whichhas been termed KSHV- or HHV-8-negativePEL, as it mostly occurs in HIV-negative in-dividuals with a median age at diagnosis of74 years (90–94), highlighting that this is adifferent disease. The consistent presence ofKSHV in what has been defined as classic PELsuggests that this virus is an etiologic agent forthe disease. However, these are uncommon tu-mors, even in populations with high incidenceof Kaposi’s sarcoma, so KSHV is evidently nec-essary but not sufficient. An important cofactorappears to be EBV, because most PELs containboth viral genomes. Analysis of the pattern ofEBV gene expression in PELs revealed that theonly EBV protein that seems to be expressedat significant levels is EBNA1, correspondingto latency I (50, 51). However, EBV miRs arealso expressed in PEL (95, 96), providing addi-tional contributory functions to PEL pathogen-esis. Although PELs have very abnormal kary-otypes, they lack structural alterations in mostcell-transforming genes frequently involved inlymphomagenesis, with the possible exceptionof mutation in the regulatory region of BCL6(71, 97). KSHV encodes a remarkable num-ber of cellular homologs with potential roles inoncogenesis (Figure 6). Some (such as a viralBCL2) are expressed during lytic infection, andmost likely are involved in keeping the cell alivelong enough to allow the virus to complete itsreplicative cycle, whereas others are expressedduring latency. Our current understanding sup-ports the notion that KSHV plays an oncogenic

role in PELs and that expression of a few viralgenes is important for proliferation and survivalof infected tumor cells. Three viral gene prod-ucts are clearly abundantly expressed in all la-tently infected cells: LANA, vCYC and vFLIP.These are encoded in a tricistronic transcriptfrom a single promoter. In addition, other viralgene products are expressed during latency inselected cell types of subsets of cells in somelesions, but are induced during lytic replica-tion, making it difficult to classify the infec-tion as latent or lytic. Among these proteins areviral proteins that appear to be important inPEL and MCD pathogenesis, specifically Ka-posin B, vIL-6, and vIRF3. The following para-graphs describe the current understanding ofthese proteins and their role in oncogenesis.

� LANA is essential for episome mainte-nance and thus functions similarly to EBVEBNA1. It can also affect several sig-naling pathways involved in oncogene-sis. It can bind and inactivate two tumor-suppressor proteins: RB1 (retinoblastomaprotein) (98) and p53 (99). LANA can alsobind and inactivate GSK3β, leading toactivation of the β-catenin pathway in-volved in solid tumors (100). Throughthis pathway, LANA can stabilize theMYC protein (101). LANA also has tran-scriptional effects on numerous viral andcellular genes, such as IL6, TERT, PIM1,and TGFBR2 (102–106). Monoclonal an-tibodies to LANA are commercially avail-able and are very useful for immunohisto-chemical diagnosis of Kaposi’s sarcoma,PEL, and MCD (107).

� vCYC (viral cyclin) is a functional cyclinthat can associate with CDK6, inducephosphorylation of RB1, and overcomecell cycle arrest (108, 109). vCYC differsfrom the cellular cyclin D in that itcan promote degradation of the CDKinhibitor CDKN1B (p27Kip1) when com-plexed with CDK6 (110, 111). Therefore,vCYC appears to modulate the cell cyclein PEL cells by circumventing normalregulatory checkpoints. vCYC transgenic



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Figure 6Representative Kaposi’s sarcoma herpesvirus (KSHV)-encoded proteins that can affect cellular proliferation, survival, differentiation,and/or angiogenesis. KSHV contains several open reading frames encoding homologs to cellular proteins involved in vital proliferativeand survival functions. Among these are � secreted autocrine/paracrine factors (vIL-6 and vMIPs); � transmembrane signalingmolecules (vGPCR and K1); � transcriptional regulators (vIRFs and LANA); � a cell cycle regulator (vCYC); � tumor-suppressorgene–binding activity (LANA); and � apoptosis inhibitors (vBCL2, vFLIP, and vIAP). Genes clearly demonstrated to be expressed inlatently infected cells in primary effusion lymphoma are shown in purple, those with some evidence of expression in latency in orange,and those expressed during lytic replication in red; cellular proteins are illustrated in blue. Adapted from Reference 167.

mice develop lymphomas, but only whenbred with TP53 knockout mice, so ithas been suggested that vCYC inducesgenomic instability and that loss of p53allows expansion of tumorigenic clones(112, 113). Supporting this hypothesis,vCYC-CDK6 complexes can inducephosphorylation of nucleophosmin(NPM1), leading to genomic instability(114, 115).

� vFLIP (ORF K13) is homologous tothe cellular FLICE/caspase 8 inhibitoryproteins (cFLIPs) (116), which can in-hibit death receptor–mediated apoptosis.However, in addition, vFLIP activatesNF-κB through both the classical and al-

ternative pathways by binding to IKKγ

and, more weakly, TRAF2 (117–120).Through activation of NF-κB, vFLIP in-duces expression of approximately 200genes, which include antiapoptotic andgrowth factor genes. Also among thetranscriptional targets of vFLIP-inducedNF-κB is cFLIP, so protection of cellsfrom Fas-induced cell death in vitro andin vivo is further enhanced (121, 122).The protection of PEL cells from spon-taneous apoptosis mediated by vFLIPis essential for tumor cell survival invitro, as demonstrated by RNA interfer-ence experiments in which knockdownof vFLIP leads to the apoptosis of PEL

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cells (122, 123). vFLIP also protects Bcells from autophagy by binding to Atg3(124). vFLIP transgenic and conditionalknockin mice develop B cell malignancieswhen the protein is expressed in B cells,and vFLIP also accelerates the devel-opment of cMYC-induced lymphomas(125–127). In addition to its antiapop-totic function, NF-κB prevents lytic re-activation (128), and vFLIP may therebycontribute to maintaining viral latency(129).

� vIRF3 (viral interferon regulatory factor3, also known as LANA2) is expressedin latency in PEL but not in Kaposi’ssarcoma. It can prevent p53 function inreporter assays (130), inactivating thistumor-suppressor pathway. AlthoughvIRF3 is not a DNA-binding protein,it can be recruited to the interferonpromoters via its interaction with cel-lular IRF3 and IRF7, stimulating theirtranscriptional activity (131).

� vIL-6 (viral interleukin-6) is a homolog ofcellular IL-6. vIL-6 differs from IL-6 inthat it is selectively glycosylated and canbind IL-6ST (previously known as IL-6receptor β or gp130) in the absence of theIL-6R (the high-affinity IL-6 receptor,also termed IL-6 receptor α or gp80) toactivate IL-6-responsive genes and pro-mote B cell survival (132–134). vIL-6 hasbeen defined as a lytic gene because its ex-pression is increased upon lytic reactiva-tion. However, it is expressed by a variablebut significant proportion of latently in-fected PEL cells as well as in MCD, and itis also expressed at low levels during truelatency (135). Because this is a secretedprotein, it can also affect other tumor cellsand other cells in the microenvironmentand play a role in their proliferation andclinical manifestations.

� Kaposins are encoded in a complex area ofthe KSHV genome that contains a smallcoding region (K12) preceded by twofamilies of two direct repeats (DR1 andDR2). This region is transcribed to po-

tentially encode three proteins: KaposinA, B, or C (136). Kaposin B encompassesDR1 and DR2 and seems to be expressedin Kaposi’s sarcoma and in some PELcells (136) but not others (137). Kaposin Bmay have transforming functions, includ-ing activation of the p38 pathway. It stabi-lizes cytokine mRNAs through activationof MK2, which in turn blocks the decay ofmRNAs with AU-rich elements (AREs)in their 3′ untranslated regions. Becauseseveral cytokine mRNAs have AREs,Kaposin B expression leads to an increasein the production of proinflammatory cy-tokines (138). Kaposin A also has been re-ported to be transforming (139) and tosignal by recruiting cytohesin-1 to theplasma membrane (140). Additional com-plexity in this locus results from RNAediting that can render the transcript en-coding Kaposins A and B nontransform-ing (141).

Two additional transmembrane proteins areencoded at the ends of the viral genome andmay be expressed in KSHV-associated LPDsand affect tyrosine kinase signaling pathways:

� K1 is a protein with an ITAM motif thatcan activate cytoplasmic tyrosine kinasesand mimic signaling by the B cell anti-gen receptor (142). K1 can activate theMAP kinase and NF-κB signaling path-ways and may have antiapoptotic func-tions (143, 144). Although K1 protein isclearly upregulated during lytic replica-tion, it is also expressed at low levels dur-ing latency (135). K1 can induce lym-phomas in common marmosets when itreplaces the saimiri transforming protein(STP) (145) and can also induce tumorsin transgenic mice (146).

� K15 contains a variable number of trans-membrane regions and cytoplasmic SH2and SH3 domains, structurally resem-bling EBV LMP2A, as well as a TRAF-binding motif. K15 activates the AKTand SRC kinases and leads to activationof the NF-κB and MAP kinase signaling



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pathways (143, 147, 148). Like EBVLMP2A, K15 can inhibit B cell receptorsignaling (149). K15 protein has beenreported to be expressed in most latentlyinfected cells (144), but the RNA expres-sion data are controversial. Most studiesare consistent with a lytic expressionpattern. K15 also has antiapoptoticfunctions (144).

KSHV encodes at least 12 pre-microRNAs,which cluster in the K12/Kaposin genomiclocus and are expressed in latently infectedcells (150–154). The function of these miRsis rapidly emerging. Recent studies have re-vealed functions that are very relevant to KSHVpathogenesis; for example miR-K1 can targetIκBα, an inhibitor of NF-κB, thereby strength-ening the NF-κB activity induced by vFLIP andpromoting cellular survival (155). miR-K1 alsotargets cellular mRNAs encoding the cellularcyclin-dependent kinase inhibitor CDKN1A(p21), thereby preventing cell cycle arrest (156).The KSHV-encoded miR-K12-11 is an or-tholog of cellular miR-155, and both the vi-ral and cellular counterparts can promote Bcell expansion (157–159). Interestingly, deepsequencing has shown that both cellular and vi-ral microRNA are present in virions, suggestingthat they can be functional immediately afterde novo infection (160). Global analyses usingthe techniques of PAR-CLIP and Ago HITS-CLIP have revealed that the KSHV miRs target1,000–2,000 cellular mRNAs in PEL cell lines,and these are enriched for genes involved inmultiple relevant pathways relevant to KSHVpathogenesis, including apoptosis, cell cycleregulation, lymphocyte proliferation, and im-mune evasion (96, 161).

CONCLUSIONS AND FUTUREPERSPECTIVES

EBV and KSHV are two lymphotropic her-pesviruses that infect lymphocytes and causelymphoproliferative disorders. That most lym-phoid neoplasms caused by these two viruses

are of B cell origin reflects their natural cel-lular tropism. These two viruses are thoughtto have coevolved with humans, and relatedviruses exist in most primates examined so far.This observation, together with the fact thatmany more people are infected than developdisease, indicates a fine evolutionary balancethat has favored the survival of both virus andhumans. However, when the balance is bro-ken, usually because of a defective immune re-sponse, problems arise. Specifically, EBV andKSHV have acquired mechanisms to ensurethat the cell they call home survives after infec-tion but is controlled by the immune system.In the absence of this immune response, theinfected cells proliferate unchecked, leading tothe development of lymphoproliferations thatcan range from controllable disease to a highlyaggressive malignancy. Our understanding ofthe mechanisms involved in this fine balancehas allowed the start of a new era during whichwe may manipulate this balance; such manipu-lation has already resulted in improved treat-ment of some patients with EBV-associatedmalignancies, namely those with PTLD, us-ing adoptive immunotherapy (162). In addi-tion, many studies to determine the mecha-nisms used by viral gene products to inducepathogenesis have revealed effects on importantcellular pathways that could be targeted, such asNF-κB, mTOR, and Notch, potentially lead-ing to improved treatment. This understand-ing has also provided a unique opportunity todevelop new therapies that directly target rele-vant viral proteins that reveal oncogenic addic-tion, and potentially also viral transcripts andmiRs. High-throughput screening methodolo-gies have been used to discover potential in-hibitors of viral oncoproteins such as EBNA1(163). Although discovery and implementationof new drugs is challenging and much too slow,future treatment of viral malignancies will likelyinvolve a combination of agents that inhibit rel-evant cellular pathways involved in viral onco-genesis and that selectively inhibit relevant viralproteins.

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DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that mightbe perceived as affecting the objectivity of this review.

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Gammaherpesviruses and Lymphoproliferative Disorders

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