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• W4247828774 abstract "Kaposi sarcoma-associated herpesvirus (KSHV) is a recently discovered and characterized member of the herpesvirus family. It is one of a few viruses proved to be associated with tumorigenesis in humans. Its causal association with 4 clinical and epidemiologic variants of Kaposi sarcoma (classic, endemic, iatrogenic, and acquired immunodeficiency virus-associated) as well as with several lymphoproliferative disorders (notably primary effusion lymphoma and multicentric Castleman disease) is reviewed critically. Issues related to the epidemiology, transmission, and molecular and serologic diagnosis are discussed. Several intriguing oncogenic mechanisms of KSHV infection have been identified. These are often dependent on the interaction of KSHV with other viruses, such as human immunodeficiency virus, Epstein-Barr virus, or both. However, important problems remain and once resolved will substantially enhance our understanding of oncogenesis in general and viral-induced oncogenesis in particular. This may also translate into improved treatment and perhaps prevention of this common and intriguing viral infection. Kaposi sarcoma-associated herpesvirus (KSHV) is a recently discovered and characterized member of the herpesvirus family. It is one of a few viruses proved to be associated with tumorigenesis in humans. Its causal association with 4 clinical and epidemiologic variants of Kaposi sarcoma (classic, endemic, iatrogenic, and acquired immunodeficiency virus-associated) as well as with several lymphoproliferative disorders (notably primary effusion lymphoma and multicentric Castleman disease) is reviewed critically. Issues related to the epidemiology, transmission, and molecular and serologic diagnosis are discussed. Several intriguing oncogenic mechanisms of KSHV infection have been identified. These are often dependent on the interaction of KSHV with other viruses, such as human immunodeficiency virus, Epstein-Barr virus, or both. However, important problems remain and once resolved will substantially enhance our understanding of oncogenesis in general and viral-induced oncogenesis in particular. This may also translate into improved treatment and perhaps prevention of this common and intriguing viral infection. In 1994, Chang et al1Chang Y Cesarman E Pessin MS et al.Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.Science. 1994; 266: 1865-1869Crossref PubMed Scopus (4976) Google Scholar identified the presence of DNA fragments of a novel herpesvirus in tumor tissue specimens from a patient with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma (KS). Within 2 years of its discovery, the 165-kilobase genome of the KS-associated herpesvirus (KSHV; also designated human herpesvirus 8) was fully sequenced.2Russo JJ Bohenzky RA Chien MC et al.Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8).Proc Natl Acad Sci U S A. 1996; 93: 14862-14867Crossref PubMed Scopus (1309) Google Scholar Soon after, the newly discovered virus was established as the primary causative factor in all types of KS, as first described in 1872 by Hungarian dermatologist Moritz Kaposi. More recently, KSHV was also linked with the pathogenesis of several lymphoproliferative disorders, and the importance of immunosuppression in the pathogenesis became recognized. Extensive virologic and epidemiologic research has not only resulted in further elucidation of molecular structure, serologic profile, and mode of viral transmission but also has provided unique insights into the mechanisms of cancer in general and virus-associated neoplasia in particular. Insight into the epidemiology of KS, the most common KSHV-associated disease, provided valuable clues to the biology of the virus and its transmission. Four clinical and epidemiologic variants of KS have been recognized3Tappero JW Conant MA Wolfe SF Berger TG Kaposi's sarcoma: epidemiology, pathogenesis, histology, clinical spectrum, staging criteria and therapy.J Am Acad Dermatol. 1993; 28: 371-395Abstract Full Text PDF PubMed Scopus (278) Google Scholar: classic, endemic (African), transplantation associated (iatrogenic), and epidemic (AIDS associated). Although all variants share KSHV-mediated pathogenesis and viral DNA can be detected in virtually all lesions of KS,4Sarid R Olsen SJ Moore PS Kaposi's sarcoma-associated herpesvirus epidemiology, virology, and molecular biology.Adv Virus Res. 1999; 52: 139-232Crossref PubMed Google Scholar several different characteristics should be recognized. Classic KS occurs predominantly in elderly men of Mediterranean or Eastern European descent and evolves slowly, sometimes over decades, starting usually on the feet and involving primarily the skin only. Endemic KS is the most frequently occurring tumor in men in certain Central African countries, whereas since the advent of AIDS, it has become more common in both sexes in Africa, with a significant lowering of the male-to-female ratio from 19:1 to 1.7:1, especially in East Africa.5Cook-Mozaffari P Newton R Beral V Burkitt DP The geographical distribution of Kaposi's sarcoma and of lymphomas in Africa before the AIDS epidemic.Br J Cancer. 1998; 78: 1521-1528Crossref PubMed Scopus (163) Google Scholar It takes a form similar to classic KS in human immunodeficiency virus (HIV)-negative adults but affects children as well in a progressive lymphadenopathic form that is often rapidly fatal. Early- life KS is extremely unusual in non-African populations. In addition, KS occurs after immunosuppressive therapy, especially in the setting of organ transplantation. This form tends to be clinically aggressive, underscoring the importance of the immune system in the outcome of KSHV infection. Indeed, discontinuation of immunosuppressive therapy has been associated with clinical remission. Up to 5% of transplant recipients in high prevalence areas but considerably fewer patients in areas with low prevalence of KSHV are affected. Iatrogenic KS results mostly from reactivation of preexisting infection; however, virus transmission from the transplanted organ has also been shown.6Sarid R Pizov G Rubinger D et al.Detection of human herpesvirus-8 DNA in kidney allografts prior to the development of Kaposi's sarcoma.Clin Infect Dis. 2001; 32: 1502-1505Crossref PubMed Scopus (30) Google Scholar AIDS-associated KS is the most prevalent form of KS today and the most common AIDS-associated cancer in the United States. It affects homosexual males (a 50% lifetime risk of developing KS before the advent of highly active antiretroviral therapy [HAART]) much more than other HIV-infected individuals with a similar degree of immunosuppression.7Katz MH Hessol NA Buchbinder SP Hirozawa A O'Malley P Holmberg SD Temporal trends of opportunistic infections and malignancies in homosexual men with AIDS.J Infect Dis. 1994; 170: 198-202Crossref PubMed Scopus (92) Google Scholar These patients exhibit a more widespread cutaneous, lymphatic, and oral involvement and may develop a frequently fatal visceral KS. The severity and progression of KS in AIDS correlate with the viral load and are inversely related to the CD4+ T-cell count.8Krown SE Testa MA Huang J AIDS Clinical Trials Group Oncology Committee AIDS-related Kaposi's sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification.J Clin Oncol. 1997; 15: 3085-3092Crossref PubMed Scopus (241) Google Scholar In general, the incidence of KS among AIDS patients has substantially declined after the introduction of HAART.9Jones JL Hanson DL Dworkin MS Jaffe HW Incidence and trends in Kaposi's sarcoma in the era of effective antiretroviral therapy.J Acquir Immune Defic Syndr. 2000; 24: 270-274PubMed Google Scholar Furthermore, KS in patients with AIDS may respond to HAART.10Dupont C Vasseur E Beauchet A CISIH 92 et al.Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients.AIDS. 2000; 14: 987-993Crossref PubMed Scopus (111) Google Scholar, 11Cattelan AM Calabrò ML Gasperini P et al.Acquired immunodeficiency syndrome-related Kaposi's sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome.J Natl Cancer Inst Monogr. 2000; 28: 44-49Crossref Google Scholar, 12Tam HK Zhang ZF Jacobson LP et al.Effect of highly active antiretroviral therapy on survival among HIV-infected men with Kaposi sarcoma or non-Hodgkin lymphoma.Int J Cancer. 2002; 98: 916-922Crossref PubMed Scopus (111) Google Scholar Primary or acute infection with KSHV has been poorly defined. To our knowledge, there is no description of characteristic symptoms that accompany primary infection in healthy individuals. A single case of an AIDS patient who seroconverted to KSHV after a transient episode of fever, lymphadenopathy, and arthralgias has been reported,13Oksenhendler E Cazals-Hatem D Schulz TF et al.Transient angiolymphoid hyperplasia and Kaposi's sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection.N Engl J Med. 1998; 338: 1585-1590Crossref PubMed Scopus (92) Google Scholar as well as 2 cases in kidney transplant recipients who developed fever, splenomegaly, cytopenia, and bone marrow failure coinciding with KSHV viremia.14Luppi M Barozzi P Schulz TF et al.Bone marrow failure associated with human herpesvirus 8 infection after transplantation.N Engl J Med. 2000; 343: 1378-1385Crossref PubMed Scopus (190) Google Scholar The KSHV seroconversion in HIV patients seems to follow a brief, low- grade viremia.15Goudsmit J Renwick N Dukers NH et al.Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997): analysis of seroconversions to ORF65 and ORF73.Proc Natl Acad Sci U S A. 2000; 97: 4838-4843Crossref PubMed Scopus (78) Google Scholar Unlike other human herpesviruses, KSHV is not ubiquitous. Seropositivity rates for KSHV show remarkable racial and geographic variations. Infection rates are less than 3% in the United States and most European countries. Infection rates are up to 25% in Mediterranean regions such as southern Italy and may be substantially more than 50% in Uganda and other Central African countries.16Schulz TF Epidemiology of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8.Adv Cancer Res. 1999; 76: 121-160Crossref PubMed Google Scholar Thus, most KSHV infections appear to be asymptomatic, and most infected individuals will not develop virus-associated disease. However, untreated HIV patients who acquire KSHV infection after HIV seroconversion are highly likely to develop KS,17Rezza G Andreoni M Dorrucci M et al.Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.J Natl Cancer Inst. 1999; 91: 1468-1474Crossref PubMed Scopus (106) Google Scholar possibly because of a synergistic effect of the 2 viruses. Specifically, Tat protein of HIV-1 has been shown to act as an angiogenic factor and as a stimulator of KSHV replication.18Harrington Jr, W Sieczkowski L Sosa C et al.Activation of HHV-8 by HIV-1 tat [letter].Lancet. 1997; 349: 774-775Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 19Fiorelli V Gendelman R Sirianni MC et al.γ-Interferon produced by CD8+ T cells infiltrating Kaposi's sarcoma induces spindle cells with angiogenic phenotype and synergy with human immunodeficiency virus-1 Tat protein: an immune response to human herpesvirus-8 infection?.Blood. 1998; 91: 956-967PubMed Google Scholar, 20Huang LM Chao MF Chen MY et al.Reciprocal regulatory interaction between human herpesvirus 8 and human immunodeficiency virus type 1.J Biol Chem. 2001; 276: 13427-13432Crossref PubMed Scopus (80) Google Scholar Therefore, HIV-1 infected individuals may be at high risk of developing KS not only because of the acquired deficiency of cellular immunity but also because of specific interactions between both viral proteins.21Weiss R Boshoff C Addressing controversies over Kaposi's sarcoma [editorial].J Natl Cancer Inst. 2000; 92: 677-679Crossref PubMed Scopus (13) Google Scholar Generally, the seroprevalence of KSHV correlates with the incidence of KS. Southern Italy's tripled seropositivity rate compared with that in northern regions mirrors KS incidence.22Whitby D Luppi M Barozzi P Boshoff C Weiss RA Torelli G Human herpesvirus 8 seroprevalence in blood donors and lymphoma patients from different regions of Italy.J Natl Cancer Inst. 1998; 90: 395-397Crossref PubMed Scopus (221) Google Scholar Nevertheless, KS seems unexpectedly uncommon in some African populations despite high KSHV seroprevalence.23Ariyoshi K Schim van der Loeff M Cook P et al.Kaposi's sarcoma in The Gambia, West Africa is less frequent in human immunodeficiency virus type 2 than in human immunodeficiency virus type 1 infection despite a high prevalence of human herpesvirus 8.J Hum Virol. 1998; 1: 193-199PubMed Google Scholar In these populations, other cofactors specifically associated with HIV-1 rather than HIV-2 infection may be implicated in the development of KS.23Ariyoshi K Schim van der Loeff M Cook P et al.Kaposi's sarcoma in The Gambia, West Africa is less frequent in human immunodeficiency virus type 2 than in human immunodeficiency virus type 1 infection despite a high prevalence of human herpesvirus 8.J Hum Virol. 1998; 1: 193-199PubMed Google Scholar This suggests that unknown cofactors may modify the clinical expression of viral infection. Genetic factors, concurrent infectious and environmental pathogens, and possibly molecular variants of KSHV that may differ in pathogenicity are probably important for establishment of KSHV-associated diseases. Sexual transmission of KSHV is well established, particularly through male homosexual contact. Thus, the prevalence of infection is associated with the number of homosexual partners and correlates with a history of sexually transmitted diseases.24Martin JN Ganem DE Osmond DH Page-Shafer KA Macrae D Kedes DH Sexual transmission and the natural history of human herpesvirus 8 infection.N Engl J Med. 1998; 338: 948-954Crossref PubMed Scopus (597) Google Scholar The risk factors for KSHV acquisition in heterosexual people are less clear. Although a reported increase in virus prevalence after puberty in developed countries further supports transmission by sexual contact, prepubertal virus prevalence observed in Africa suggests additional modes of transmission.25Plancoulaine S Abel L van Beveren M et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar Horizontal mother-to-child transmission of KSHV,25Plancoulaine S Abel L van Beveren M et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar transmission via saliva,26Pauk J Huang ML Brodie SJ et al.Mucosal shedding of human herpesvirus 8 in men.N Engl J Med. 2000; 343: 1369-1377Crossref PubMed Scopus (379) Google Scholar and other, presently unknown routes of transmission are suggested. Periodic salivary shedding of KSHV has been recorded,26Pauk J Huang ML Brodie SJ et al.Mucosal shedding of human herpesvirus 8 in men.N Engl J Med. 2000; 343: 1369-1377Crossref PubMed Scopus (379) Google Scholar and primary human keratinocytes have been shown to support KSHV infection and replication, consistent with the notion that epithelial cells in mucosal sites are likely to be a primary site of infection.27Cerimele F Curreli F Ely S Friedman-Kien AE Cesarman E Flore O Kaposi's sarcoma-associated herpesvirus can productively infect primary human keratinocytes and alter their growth properties.J Virol. 2001; 75: 2435-2443Crossref PubMed Scopus (60) Google Scholar Familial KS is extremely rare. Nevertheless, interfamilial transmission of KSHV was recently suggested,28Davidovici B Karakis I Bourboulia D et al.Seroepidemiology and molecular epidemiology of Kaposi's sarcoma-associated herpesvirus among Jewish population groups in Israel.J Natl Cancer Inst. 2001; 93: 194-202Crossref PubMed Scopus (98) Google Scholar and family members of KS patients have a 3-fold higher KSHV seroprevalence rate compared with the general population.29Angeloni A Heston L Uccini S et al.High prevalence of antibodies to human herpesvirus 8 in relatives of patients with classic Kaposi's sarcoma from Sardinia.J Infect Dis. 1998; 177: 1715-1718Crossref PubMed Scopus (81) Google Scholar Although KSHV can probably be transmitted by organ transplantation, evidence supporting blood-borne transmission is still relatively poor.30Blackbourn DJ Ambroziak J Lennette E Adams M Ramachandran B Levy JA Infectious human herpesvirus 8 in a healthy North American blood donor.Lancet. 1997; 349: 609-611Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 31Cannon MJ Dollard SC Smith DK HIV Epidemiology Research Study Group et al.Blood-borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection.N Engl J Med. 2001; 344: 637-643Crossref PubMed Scopus (157) Google Scholar Even among HIV-positive patients, the prevalence of KS in hemophilia patients, intravenous drug users, and transfusion recipients is low, and recipients of bone marrow transplants also show no increased rate of infection.32Rosenzwajg M Fery N Bons V Damaj G Gluckman E Gluckman J Human herpes virus 8 (HHV8) serology in allogeneic bone marrow transplant recipients.Bone Marrow Transplant. 1999; 24: 351-354Crossref PubMed Scopus (24) Google Scholar Because virus sequences have been detected in peripheral blood mononuclear cells and plasma of KS patients,33Whitby D Howard MR Tenant-Flowers M et al.Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma.Lancet. 1995; 346: 799-802PubMed Scopus (819) Google Scholar large-scale screening of blood donors and parallel analysis of recipients in areas endemic for KSHV may clarify the actual effect of blood-borne transmission. The first diagnostic tool in the detection of KSHV infections was based on the use of polymerase chain reaction (PCR) to amplify viral DNA1Chang Y Cesarman E Pessin MS et al.Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.Science. 1994; 266: 1865-1869Crossref PubMed Scopus (4976) Google Scholar (Figure 1). Southern blot hybridization is being used as an additional confirmatory test. Each detects viral DNA in virtually all lesions of KS, providing one of many other clues and firmly establishing causal relationship.4Sarid R Olsen SJ Moore PS Kaposi's sarcoma-associated herpesvirus epidemiology, virology, and molecular biology.Adv Virus Res. 1999; 52: 139-232Crossref PubMed Google Scholar The PCR studies were also applied to determine and quantify the presence of KSHV DNA in tissues and bodily fluids. Tissue localization of the virus can be further studied by immunohistochemical and in situ hybridization techniques. At the same time genetic variability of the virus is being increasingly recognized, although its clinical importance remains uncertain.34Zong JC Ciufo DM Alcendor DJ et al.High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations.J Virol. 1999; 73: 4156-4170PubMed Google Scholar These types of studies suggest that KSHV is an ancient human virus principally transmitted in a familial mode with low recombination rates.34Zong JC Ciufo DM Alcendor DJ et al.High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations.J Virol. 1999; 73: 4156-4170PubMed Google Scholar Serologic assays are currently used in research laboratories to diagnose infection. Antibody response persists for the lifetime of the patient and may therefore be used to establish the prevalence of infection and evaluate risk factors for transmission. Serologic assessment may also be important for surveillance and prevention of KSHV-related diseases, predominantly in organ transplantation in areas of high prevalence and in HIV-infected patients. Various formats of diagnostic serologic tests already exist; however, only a few are commercially available. Initial widely used serologic tests use immunofluorescence assays to detect antibodies to latent or lytic viral antigens expressed in KSHV-infected cell lines derived from patients with primary effusion lymphoma35Gao SJ Kingsley L Li M et al.KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma.Nat Med. 1996; 2: 925-928Crossref PubMed Scopus (721) Google Scholar, 36Kedes 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 [published correction appears in Nat Med. 1996;2:1041].Nat Med. 1996; 2: 918-924Crossref PubMed Scopus (656) Google Scholar, 37Lennette ET Blackbourn DJ Levy JA Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients.Lancet. 1996; 348: 858-861Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar (Figure 1). However, interobserver differences may produce a variation in the results. Several enzyme-linked immunosorbent assays (ELISAs) were also established by using purified recombinant KSHV immunogenic lytic antigens (open reading frame [ORF] 65, 26, K8.1) or latent antigens (ORF 73, K12).38Rabkin CS Schulz TF Whitby D et al.HHV-8 Interlaboratory Collaborative GroupInterassay correlation of human herpesvirus 8 serologic tests.J Infect Dis. 1998; 178: 304-309Crossref PubMed Scopus (159) Google Scholar, 39Schatz O Monini P Bugarini R et al.Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicentre study with multiple and novel assays.J Med Virol. 2001; 65: 123-132Crossref PubMed Scopus (66) Google Scholar Additional ELISAs with one peptide selected from an immunogenic viral protein, a mixture of peptides, or a whole virus were developed.38Rabkin CS Schulz TF Whitby D et al.HHV-8 Interlaboratory Collaborative GroupInterassay correlation of human herpesvirus 8 serologic tests.J Infect Dis. 1998; 178: 304-309Crossref PubMed Scopus (159) Google Scholar, 39Schatz O Monini P Bugarini R et al.Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicentre study with multiple and novel assays.J Med Virol. 2001; 65: 123-132Crossref PubMed Scopus (66) Google Scholar Immunoblotting techniques have been applied for most of these antigens. A sensitive and specific “gold standard” method for identifying infected individuals has not yet been established. Several large studies15Goudsmit J Renwick N Dukers NH et al.Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984-1997): analysis of seroconversions to ORF65 and ORF73.Proc Natl Acad Sci U S A. 2000; 97: 4838-4843Crossref PubMed Scopus (78) Google Scholar, 38Rabkin CS Schulz TF Whitby D et al.HHV-8 Interlaboratory Collaborative GroupInterassay correlation of human herpesvirus 8 serologic tests.J Infect Dis. 1998; 178: 304-309Crossref PubMed Scopus (159) Google Scholar, 39Schatz O Monini P Bugarini R et al.Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicentre study with multiple and novel assays.J Med Virol. 2001; 65: 123-132Crossref PubMed Scopus (66) Google Scholar compared the performance of the various serologic assays. The concordance for KS sera is relatively high, whereas it decreases in healthy individuals, African patients, and KS-free HIV-infected patients. Because certain serologic methods couple increased sensitivity with a decreased specificity and vice versa, a higher predictive value is achievable with combinations, preferably with antigens representing both lytic and latent virus proteins.39Schatz O Monini P Bugarini R et al.Kaposi's sarcoma-associated herpesvirus serology in Europe and Uganda: multicentre study with multiple and novel assays.J Med Virol. 2001; 65: 123-132Crossref PubMed Scopus (66) Google Scholar Interestingly, recent data suggest that a combined increase in PCR and antibody signals may predict KS onset.40Campbell TB Borok M Gwanzura L et al.Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage.AIDS. 2000; 14: 2109-2116Crossref PubMed Scopus (121) Google Scholar The development of a universal algorithm for a routine serologic diagnosis is pending and remains a highly important goal. Together with human T-cell lymphotropic virus 1, hepatitis B virus, hepatitis C virus, human papillomavirus, and Epstein-Barr virus (EBV), KSHV is capable of inducing malignant tumors in humans. Like other oncogenic viruses, KSHV has evolved various mechanisms for immortalizing and transforming cells (Figure 2). Its viral genome contains several genes that are homologous to protooncogenes, cellular genes capable of inducing malignant tumors.4Sarid R Olsen SJ Moore PS Kaposi's sarcoma-associated herpesvirus epidemiology, virology, and molecular biology.Adv Virus Res. 1999; 52: 139-232Crossref PubMed Google Scholar, 41Moore PS Chang Y Antiviral activity of tumor-suppressor pathways: clues from molecular piracy by KSHV.Trends Genet. 1998; 14: 144-150Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Thus, a viral homologue of cyclin D can inhibit the retinoblastoma tumor-suppressor protein.42Li M Lee H Yoon DW et al.Kaposi's sarcoma-associated herpesvirus encodes a functional cyclin.J Virol. 1997; 71: 1984-1991Crossref PubMed Google Scholar, 43Swanton C Mann DJ Fleckenstein B Neipel F Peters G Jones N Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins.Nature. 1997; 390: 184-187Crossref PubMed Scopus (299) Google Scholar, 44Godden-Kent D Talbot SJ Boshoff C et al.The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1.J Virol. 1997; 71: 4193-4198Crossref PubMed Google Scholar Furthermore, the cellular inhibitors of this pathway (p16, p21, and p27) do not inhibit the virally encoded cyclin D protein.43Swanton C Mann DJ Fleckenstein B Neipel F Peters G Jones N Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins.Nature. 1997; 390: 184-187Crossref PubMed Scopus (299) Google Scholar Concomitantly, other viral genes, such as the latency-associated nuclear antigens 1 and 2 and viral interferon regulatory factors, interfere with the p53 tumor suppressor pathways, which regulate cellular senescence and apoptosis.45Friborg Jr, J Kong W Hottiger MO Nabel GJ p53 inhibition by the LANA protein of KSHV protects against cell death.Nature. 1999; 402: 889-894Crossref PubMed Scopus (581) Google Scholar, 46Rivas C Thlick AE Parravicini C Moore PS Chang Y Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53.J Virol. 2001; 75: 429-438Crossref PubMed Scopus (255) Google Scholar, 47Nakamura H Li M Zarycki J Jung JU Inhibition of p53 tumor suppressor by viral interferon regulatory factor.J Virol. 2001; 75: 7572-7582Crossref PubMed Scopus (115) Google Scholar, 48Gao SJ Boshoff C Jayachandra S Weiss RA Chang Y Moore PS KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway.Oncogene. 1997; 15: 1979-1985Crossref PubMed Scopus (318) Google Scholar Certain viral genes homologous to cellular antiapoptotic genes may facilitate malignant transformation.49Sarid R Sato T Bohenzky RA Russo JJ Chang Y Kaposi's sarcoma-associated herpesvirus encodes a functional bcl-2 homologue.Nat Med. 1997; 3: 293-298Crossref PubMed Scopus (305) Google Scholar, 50Cheng EH Nicholas J Bellows DS 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: 690-694Crossref PubMed Scopus (398) Google Scholar, 51Thome M Schneider P Hofmann K et al.Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors.Nature. 1997; 386: 517-521Crossref PubMed Scopus (1142) Google Scholar In addition, viral chemokines and cytokines, such as interleukin 6, have numerous tumorfacilitating effects, including an effect on B cells and a possible induction of angiogenesis, which may contribute to the pathogenesis of the KS lesion.52Moore PS Boshoff C Weiss RA Chang Y Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV.Science. 1996; 274: 1739-1744Crossref PubMed Scopus (822) Google Scholar A transformed phenotype was obtained when the virus G protein-coupled receptor homologue protein or the unique Kaposin protein was overexpressed in vitro.53Bais C Santomasso B Coso O et al.G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator.Nature. 1998; 391: 86-89Crossref PubMed Scopus (749) Google Scholar, 54Cesarman E Mesri EA Gershengorn MC Viral G protein-coupled receptor and Kaposi's sarcoma: a model of paracrine neoplasia?.J Exp Med. 2000; 191: 417-422Crossref PubMed Scopus (131) Google Scholar, 55Muralidhar S Pumfery AM Hassani M et al.Identification of kaposin (open reading frame K12) as a human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) transforming gene [published correction appears in J Virol. 1999;73:2568].J Virol. 1998; 72: 4980-4988Crossref PubMed Google Scholar, 56Kliche" @default.
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• W4247828774 title "Virology, Pathogenetic Mechanisms, and Associated Diseases of Kaposi Sarcoma-Associated Herpesvirus (Human Herpesvirus 8)" @default.
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