Kaposi's sarcoma and other manifestations of human herpesvirus 8

CONTINUING

MEDICAL EDUCATION

Kaposi’s sarcoma and other manifestations of human herpesvirus 8 Pedram Geraminejad, MD,a Omeed Memar, MD, PhD,a Iris Aronson, MD,a Peter L. Rady, MD, PhD,b Ulrich Hengge, MD, PhD,c and Stephen K. Tyring, MD, PhDb Chicago, Illinois, Galveston, Texas, and Du ¨ sseldorf, Germany Kaposi’s sarcoma (KS) was described by Moritz Kaposi in 1872 and was known for an entire century as a rare disorder of older men usually of Eastern European, Mediterranean, and/or Jewish origin. In the early 1980s, the prevalence of KS began to increase dramatically and soon became the most common malignancy in patients with AIDS, especially those who were male homosexuals. In 1994, a new human herpesvirus (HHV) was found to be present in almost 100% of KS lesions. This virus was found to be a gammaherpesvirus, closely related to Epstein-Barr virus, and was designated HHV-8. Subsequently, HHV-8 DNA was found in almost all specimens of classic KS, endemic KS, and iatrogenic KS, as well as epidemic KS (ie, AIDS KS). It is now believed that HHV-8 is necessary, but not sufficient, to cause KS and that other factors such as immunosuppression play a major role. The use of highly active antiretroviral therapy (HAART) since 1996 has markedly reduced the prevalence of AIDS KS in western countries, but because 99% of the 40 million patients with AIDS in the world cannot afford HAART, KS is still a very common problem. Primary effusion lymphoma and multicentric Castleman’s disease are also thought to be due to HHV-8. Although HHV-8 DNA has been described in a number of other cutaneous disorders, there is little evidence that HHV-8 is of etiologic significance in these diseases. The mechanism by which HHV-8 causes KS, primary effusion lymphoma, and multicentric Castleman’s disease is not well understood but is thought to involve a number of molecular events, the study of which should further our understanding of viral oncology. (J Am Acad Dermatol 2002;47:641-55.)

Learning objective: At the completion of this learning activity, participants should be familiar with Kaposi’s sarcoma and other manifestations of human herpesvirus 8.

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efore 1980, Kaposi’s sarcoma (KS) was primarily known as a disease of older males of Eastern European, Mediterranean, or Jewish background. In the early 1980s, KS was found in approximately 40% of American men with AIDS.1 Cross-sectional analysis of the population with AIDS KS revealed that the affected population was primarily homosexual men. This phenomenon attracted much publicity to AIDS KS, and hence, the other

From the Department of Dermatology, University of Illinois at Chicagoa; the Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas Medical Branchb; and the Department of Dermatology, Heinrich-Heine University, Du¨sseldorf.c Funding sources: None. Conflict of interest: None identified. Reprint requests: Stephen K. Tyring, MD, PhD, University of Texas Medical Branch for Clinical Studies, 2060 Space Park Dr, Houston, TX 77058. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/2/128383 doi:10.1067/mjd.2002.128383

Abbreviations used: CDK: EBV: ␤-FGF: FLIP:

cyclin-dependent kinase Epstein-Barr virus ␤-fibroblast growth factor Fas-ligand–interleukin 2–converting enzyme inhibitor protein HAART: highly active antiretroviral therapy HHV: human herpesvirus KS: Kaposi’s sarcoma LANA: latency-associated nuclear antigen MCD: multicentric Castleman’s disease MM: multiple myeloma ORF: open reading frame PCR: polymerase chain reaction PEL: primary effusion lymphoma PI: protease inhibitor POEMS: polyneuropathy, organomegaly, endocrinopathy, multiple myeloma, skin changes

variants of KS: classic, endemic, and transplant-associated KS. Although phenotypic features are relatively consistent within the 4 subtypes, the clinical course varies.2 The epidemiology of KS in the AIDS 641

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population strongly suggested an infectious agent. In 1994, Chang et al,3 using representational difference analysis, a novel technique used to determine subtle differences in DNA sequences between two genomes, discovered an uncanny association between a previously unknown virus and KS. This includes all subtypes of KS. This virus was named Kaposi’s sarcoma–associated herpesvirus (KSHV), and it was subsequently designated the eighth human herpesvirus, HHV-8. Since then, HHV-8 has also been definitively linked with primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). Currently, much debate exists regarding its involvement in a variety of other entities and its mechanisms of pathology.4,5 With rare exceptions, KS is not considered a true malignancy or cancer, but rather a virus-induced cellular proliferation. Although evidence for true oncogenicity and true transformation is lacking in KS, we use the words transformation and oncogenicity in this review for consistency. We offer a systematic review of the molecular biology and oncology of HHV-8 and the data regarding the involvement of HHV-8 in a heterogeneous spectrum of diseases.

CHARACTERIZATION OF A NEW HERPESVIRUS Herpesviruses are double-stranded DNA viruses known to be highly disseminated in nature. Among the 100 or more herpesviruses that have been recognized, only 7 had been isolated from humans until recently. The study of herpesviruses has uncovered certain similarities within the family. First, herpesviruses express a wide array of enzymes that take part in nucleic acid metabolism (eg, thymidine kinase, thymidylate kinase, thymidylate synthetase, dUTPase, or ribonucleotide reductase), DNA synthesis (eg, DNA polymerase, helicase, or primase), and posttranslational modification (eg, protein kinase). Second, herpes viral DNA synthesis and capsid assembly occur in the nucleus. Third, production of infectious progeny virus is often coincident with the death of the infected cell. Lastly, herpesviruses can exist in either lytic or latent states. In the latent state, the viral genome may exist as an episome only expressing a selective group of viral genes. Various stressors such as ultraviolet light or immunosuppression can reactivate latent herpesviruses into the lytic state, which can produce a myriad of disease states. Factors such as tissue tropism, genetic structure, cytopathology, site of infection, and pathogenesis, as well as presentation of disease, allow for phylogenic classification of viruses. Human herpesviruses are classified into 3 subfamilies (Fig 1). These are known as alphaherpesvirinae consisting of herpes

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simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus; betaherpesvirinae consisting of cytomegalovirus, HHV-6, and HHV-7; and gammaherpesvirinae consisting of Epstein-Barr virus (EBV). Gammaherpesviruses are known for their associations with cancer and cellular proliferation. On the basis of the criteria described previously including tissue tropism, HHV-8, like EBV, is classified as a gammaherpesvirus.6 Within the gammaherpesvirinae, HHV-8 is further classified as a ␥2 or rhadinovirus.6 It shares the highest degree of homology with rhadinoviruses in large primates, and to a lesser degree, with herpesvirus saimiri of new world primates. It is believed that HHV-8 is a naturally co-evolved human version of the herpesvirus saimiri.7

EPIDEMIOLOGY Ninety to one hundred percent of patients with KS have high antibody titers to HHV-8, independent of ethnicity and geographic location.8 The seroprevalence varies widely in general populations from different geographic areas. The highest seroprevalence of HHV-8 is seen in African countries. It is near 100% in the Ivory Coast; 89% in Gambia; 40% in sub-Saharan Africa; 10% in Mediterranean countries; 2% to 4% in Northern Europe, Southeast Asia, and Caribbean countries; and from 5% to 25% (most reports are closer to 5%) in the heterogeneous United States.8,9 A large study on blood donors from different regions of Italy showed that HHV-8 seroconversion ranged from 3.8% to 35%.10 The incidence of KS is highest in those areas with the highest seroprevalence of HHV-8 with some exceptions. Although in sub-Saharan Africa the 40% seroprevalence correlates well with the high incidence of endemic KS, this is not true for the Ivory Coast or Gambia.6 Although the seroprevalence in these countries is extremely high, the incidence of KS is minimal, and endemic KS is not known in these regions. A similar finding among BrazilianAmerindians has been published; seroprevalence was 53%, although KS has never been reported in this population.11 Overall, the differences in seroprevalence of HHV-8 in general populations can represent the geographic and/or ethnic distribution of the virus. The different data from similar populations can be explained by the different serologic methods and serum dilutions used.12 Within the United States, KS is most commonly seen in homosexual men with AIDS.13 At one time, 40% of this population was reported to have KS. This is a 20-fold increase over nonhomosexual patients with AIDS, implicating a sexual mode of transmis-

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Fig 1. Herpesvirinae family tree and characteristics. CMV, Cytomegalovirus; MCD, multicentric Castleman’s disease; PEL, primary effusion lymphoma.

sion.14 In fact, epidemiologic studies have consistently identified the following risk factors for an increased incidence of KS: increased number of sexual partners, HIV-1 seropositivity, history of hepatitis A, a history of other sexually transmitted diseases such as HSV-2,13 and receptive anal intercourse.15-17 Similarly, the risk of seroconversion to HHV-8 has been shown to increase with duration of homosexual activity, oral genital contact, insertive and receptive anal intercourse, and insertive and receptive analingus.15-17 One population-based study in San Francisco illustrated a linear relationship between number of male sexual intercourse partners in the last 2 years and HHV-8 seroprevalence.18 A sexual mode of transmission among homosexuals seems highly likely when these data and the readily detectable presence of HHV-8 in semen and saliva are considered.15,19 Among heterosexuals, a predominant mode of HHV-8 transmission is less evident. Several studies have shown that women with HIV-1 infection have higher seroprevalences of HHV-8 than HIV-1–negative women and that women engaged in prostitution have higher HHV-8 seroprevalences.20,21 However, data from areas where HHV-8 is endemic support a

nonsexual horizontal mode of transmission. Several African countries report an increasing seroprevalence of HHV-8 with increasing age among prepubertal children. For example, in Gambia, the incidence rose from 9% in 0 to 7-year-olds to 33% in 10to 14-year-olds.22 Similar data have been reported in Uganda and Cameroon. Significant clustering of HHV-8 is seen in families and children of HHV-8 – infected mothers after the children are at least 2 years of age and no longer protected by maternal antibodies.16 Although a quantifiable measurement of the importance of this nonsexual horizontal means of transmission relative to sexual transmission among heterosexuals is unavailable, an obvious role does exist.

CLINICAL VARIANTS OF KAPOSI’S SARCOMA Classic Kaposi’s sarcoma Classic KS primarily occurs in older men of Eastern European, Mediterranean, or Jewish descent. The male/female ratio has been reported to be anywhere between 15:1 and 3:1.2 More than 65% of patients are older than 50 years at the time of diagnosis.1 Bluish-red macules or papules on the distal

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prepubertal children with no sex predilection.24 These children commonly present with localized or generalized lymphadenopathy. Rapid visceral involvement can cause early death. Skin lesions are sparse.2 Iatrogenic Kaposi’s sarcoma Severe immunosuppression, such as that which occurs iatrogenically with medications in organ transplantation or autoimmunity and in those patients with malignancy, predisposes to KS. This is especially true for male patients of Eastern European, Mediterranean, or Jewish origin. The lesions typically appear several years after transplantation in transplant recipients who have received high doses of immunosuppressive agents.25,26 The clinical course is variable, depending on the degree of immunosuppression. With lower doses, the course may resemble that of classic KS, and the lesions commonly regress when the medications are reduced or discontinued. Higher doses can lead to a more fulminant picture.26,27 Both molecular and serologic evidence of HHV-8 activation has been reported in transplant recipients.28

Fig 2. Nodules of classic Kaposi’s sarcoma on foot of an elderly Italian man.

lower extremities are often the first sign of KS. Confluence of the lesions may eventually result in patches or plaques. Unilateral involvement soon becomes bilateral; as the patches and plaques disseminate to become multifocal, nodules often result from further coalescence of the lesions (Fig 2). Edema of the surrounding tissue is common and may occur before or after the appearance of the actual KS lesion. The process is slow and the course is benign. Visceral or mucosal involvement is found in 10% of patients.2 Endemic Kaposi’s sarcoma Endemic KS, also known as African KS, exists in 4 clinical subvariants: nodular, florid, infiltrative, and lymphadenopathic. The nodular variant resembles classic KS. The florid or infiltrative types are more aggressive. The lymphadenopathic form is particularly common among the young Bantu children of South Africa, the same geographic location of Burkitt’s lymphoma.23 Although the other African subvariants of KS have a male to female ratio similar to that of classic KS and a mean age of onset of 48 years, the lymphadenopathic form is seen mostly in

Epidemic Kaposi’s sarcoma AIDS-associated or epidemic KS is the most common AIDS-associated malignancy.29 The prevalence of epidemic KS is approximately 20-fold higher in homosexual men than in other HIV risk groups.14 This value has been decreasing in recent years because of safer sexual practices, awareness of sexually transmitted diseases, and the use of highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) in patients with AIDS.30-32 In numerous case reports and prospective studies, complete remission of KS has been described after the administration of HAART with PIs.31-33 It is very difficult to assess whether PIs confer a direct antiviral effect on HHV-8. In a recent study it was reported that the HIV PIs act as potent anti-angiogenic molecules by blocking basic fibroblast growth factor– and/or vascular endothelial growth factor–induced angiogenesis.34 Some investigators have reported an association between decreased HHV-8 viral load in peripheral blood mononuclear cells and regression of KS with PI therapy.35 However, at this time no data clearly indicate whether this is secondary to improvement in the CD4 cell count and HIV-1 viral load or direct activity against HHV-8. Furthermore, the variables most consistently and highly correlated with KS regression are an increasing CD4 cell count and decreasing HIV-1 viral load, whereas the relationship of HHV-8 viral load and KS regression is less consistent and often variable.30-32 Likewise, a persis-

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Fig 4. Plaques of epidemic Kaposi’s sarcoma on hard and soft palate of an HIV-seropositive man before initiation of highly active antiretroviral therapy.

DIFFERENTIAL DIAGNOSES A number of other vascular tumors may mimic KS clinically and/or histologically. Such conditions range from the common pyogenic granuloma (Fig 6) to the rare hemangiopericytoma. Of particular interest are the other vascular lesions of infectious (ie, bacterial) etiology such as bacillary angiomatosis (Fig 7) and verruca peruana (Fig 8); proper diagnosis usually requires correlation of the clinical and histologic findings. Fig 3. Widespread plaques and nodules of epidemic Kaposi’s sarcoma on leg of an HIV-seropositive man before initiation of highly active antiretroviral therapy.

tently elevated HIV-1 RNA level is a key feature of those patients with KS who progress to later stages of disease.31 Therefore, although the status of the immune system and HIV-1 viral load seem to be of primary importance, a direct anti–HHV-8 response for PIs has not been proven. In contrast to the classic form, in AIDS KS, early lesions commonly appear on the face, especially on the nose, eyelids, and ears. On the trunk the lesions may follow the lines of cleavage. The early lesions appear as reddish to pink macules and papules. Only in prolonged courses do the macules and papules sufficiently coalesce to form larger plaques (Fig 3). The lymph nodes and the gastrointestinal tract are commonly involved.36 The oral mucosa is the initial site of disease in 10% to 15% of patients, usually on the palate (Fig 4).2 Genital lesions are not uncommon (Fig 5). The disease usually runs a protracted course and is not a common cause of death in patients with AIDS. Pulmonary involvement, which is uncommon, can be more serious and cause progressive respiratory insufficiency.36,37

ASSOCIATED PATHOLOGY Kaposi’s sarcoma A recent literature review showed that in a compilation of 21 studies, polymerase chain reaction (PCR) evidence for the presence of HHV-8 in KS lesions was approximately 95%.38 This was independent of whether the lesions were classical, AIDS/ epidemic, endemic, or the childhood type. Among these studies was the original work of Chang et al3 who found, in a series of 27 KS lesions, 25 to be PCR-positive for HHV-8. Other researchers have reported similar findings,39-41 including some studies with PCR evidence of HHV-8 in 100% of KS biopsy specimens.42 In one very well documented case report, serum samples from a homosexual man were obtained 14, 7, and 4 months, as well as 5 weeks before the onset of KS lesion formation. Serum was then obtained 2 weeks, 8 months, and 7 years after onset. Serum samples were negative for anti–HHV-8 antibodies until 5 weeks before onset and remained positive.43 PCR analysis of the KS lesions and lymph node biopsy specimens was also done, verifying the presence of HHV-8. This retrospective study shows an excellent temporal association with HHV-8 and KS. In vitro and in vivo studies substantiate the role of HHV-8 in KS. Dermal microvascular entodermal

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Fig 6. Pyogenic granuloma of heel.

Fig 5. Nodules of epidemic Kaposi’s sarcoma of vagina and labia minora in an HIV-seropositive woman who did not respond to highly active antiretroviral therapy. Although genital KS is not uncommon in HIV-seropositive men, the prevalence of KS at any location is 20-fold lower in HIV-seropositive women. (Photograph courtesy of Concepcion Arrastia, MD, Department of Obstetrics and Gynecology, University of Texas Medical Branch.)

cells exposed to an active source of HHV-8 developed a spindle shape resembling that of KS spindle cells in vivo (Fig 9).44 The cells displayed elements of a transformed phenotype including contact inhibition, acquisition of anchorage-independent growth, and selective loss of endothelial markers. These are typical findings of the spindle cells in actual KS lesions. PCR also showed that similar to actual KS lesions, although the majority of cells were latently infected, a small percentage of spindle cells showed lytic infection. Furthermore, cell lines developed from KS lesions form vascular tumors when implanted in mice.45 The compilation of data in favor of a role for HHV-8 in KS is impressive. Primary effusion lymphoma Primary effusion lymphoma (PEL) is a rare B-cell lymphoma, seen predominantly in patients with

Fig 7. Bacillary angiomatosis in an HIV-seropositive man.

Fig 8. Verruca peruana in a child from Peru. (Photograph courtesy of Francisco Bravo, MD, Lima, Peru.)

AIDS. Most PELs are thought to originate from postgerminal center B cells. Because they have hypermutation of the immunoglobulin genes, PELs usually lack expression of B-cell–associated antigens, although most of them express kappa or lambda messenger RNA. In fact, some cases have been reported

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to express surface or cytoplasmic immunoglobulin.46 Most PELs also express CD 138/syndecan I, an adhesion molecule that is selectively expressed by a subset of pre-B cells and by plasma cells.46 HHV-8 infection of postgerminal B cells is responsible for PELs.47-50 Cesarman and Knowles51 evaluated the presence of HHV-8 in a large spectrum of 193 lymphoid malignancies. Among these were 8 AIDS-related PELs, all of which were found to be positive for HHV-8 by PCR. Impressively, not one of the remaining 185 lymphoid malignancies consisting of both AIDS- and non–AIDS-related, nonHodgkin’s, Hodgkin’s, and lymphoid leukemia contained HHV-8. Another important feature of PELs is that the viral DNA copy number is extremely high, between 40 and 80 copies, compared with their KS counterparts. This high copy number is unique to PELs, and lesions with lower copy numbers are probably of a different pathology.51 HHV-8 is consistently found in PELs, whereas other viruses are not. Most of the initial PELs were positive for both HHV-8 and EBV.52 In 1998, the first HHV-8⫹/EBV– cell line was described.53 Studies with HHV-8⫹/EBV– cell lines highly support HHV-8⫹ as the causative agent of PEL. In a comprehensive literature review of cell lines established from solid and hematopoietic malignancies, HHV-8 was the only virus found to be present in all PELs in the pool.54 Significantly, HHV-8 was not present in any of the other cell lines. Cells from BCP-1, an HHV-8⫹/EBV– cell line, have been used for heterotransplantation to NOD/SCID mice (nonobese diabetic/severe combined immunodeficiency). All injected mice developed lymphomatous effusions similar to PEL.53 Microscopic lymphomatous infiltration was seen in the kidneys, liver, pancreas, spleen, lungs, and heart but not in the brain. The presence of HHV-8 was confirmed by using Southern blot hybridization. This novel study provides a complete animal model as described by Koch’s postulates. Multicentric Castleman’s disease Castleman’s disease is a rare, nonmalignant lymphoproliferative disorder, characterized by atypical polyclonal B cells, in a microenvironment of excess interleukin-6 (IL-6).55 Two forms predominate: (1) localized Castleman’s disease, which usually presents in mediastinal or other lymph nodes, and (2) MCD with significant systemic involvement and generalized lymphadenopathy.47 Both forms commonly present with fever, anemia, and hypergammaglobulinemia possibly caused by elevated IL-6 levels. Histologically, Castleman’s disease can be divided into a plasma cell (PC) variant type, a hyaline vascular type, or a combination of the two. The multicentric

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Fig 9. Histopathologic findings of Kaposi’s sarcoma. A proliferation of spindle-shaped cells is seen within the interstitium of the dermis. These cells outline small, irregular slits and clefts. Tumor cells are moderately pleomorphic with uniformly hyperchromic nuclei. Rare hyaline globules are seen in the cytoplasm. (Hematoxylin-eosin stain; original magnification ⫻400.)

PC and multicentric PC-hyaline types are most likely manifestations of HHV-8.46 MCD of the PC or PC-hyaline type is commonly seen in HIV-infected individuals and is secondary to infection with HHV-8. Most case studies demonstrate near 100% presence of HHV-8 by PCR in AIDS-associated MCD, whereas studies of non– AIDS-related MCD show HHV-8 in 40% to 50% of cases.46,55-57 The cellular homologues present in HHV-8 include an IL-6 –like viral protein. IL-6 is a cytokine that enhances B-cell survival and proliferation. It is speculated that the expression of this gene may be involved in the pathogenesis of MCD and PEL.55,58,59 Elevated levels of IL-6 within MCD lesions have been well documented. Plasmablastic MCD is another variant of MCD, which has not yet been well characterized but has also been highly associated with HHV-8.60 POEMS syndrome POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, multiple myeloma, skin changes) is commonly coexistent with MCD. High levels of IL-6 have also been reported.61 This was cause for suspicion of a causal link to HHV-8. The presence of HHV-8 has rarely been reported in POEMS syndrome when concomitant MCD is not present.62 Therefore, at this time, another agent or mechanism of disease for this entity must be pursued.

OTHER DISEASES WITH REPORTED ASSOCIATIONS WITH HHV-8 Several early reports suggested a role of HHV-8 in multiple myeloma (MM) by means of both PCR and

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in situ hybridization with an HHV-8-specific probe. These investigations included cells in long-term culture, as well as fresh bone marrow biopsy specimens from patients with MM.63,64 However, subsequent studies failed to detect HHV-8 DNA or anti-HHV-8 antibodies in patients with MM.65-71 Likewise, studies of a variety of epithelial lesions in immunocompromised patients produced evidence of HHV-8 DNA by means of PCR,72-76 but other reports showed that the prevalence of HHV-8 in such lesions was comparable to that in normal skin.77-84 A variety of vascular tumors, such as angiosarcoma, have occasionally been associated with HHV-8, but the prevalence of the virus has been low in most investigations.85-88 Although HHV-8 has been demonstrated in a variety of forms of pemphigus,89,90 results of most studies have been negative.91-95 Thus, KS, PEL, and MCD remain the only 3 diseases in which an etiologic relationship with HHV-8 is accepted.

MOLECULAR BIOLOGY AND ONCOLOGY OF HHV-8 Viral oncology is one of the most challenging areas of virology. Various mechanisms of oncogenicity have been proposed for specific DNA viruses. Unfortunately, a universal model consistent with the independent findings currently present for the known DNA oncogenic viruses is not applicable. It is predominately believed that there are two primary requirements for a DNA virus to cause cell transformation. First, the virus must be integrated into the host genome. Second, a change in gene expression from the host should occur. This change in expression can be extremely complex. This change may be due to the combination of various viral or cellular oncogenes or tumor suppressor genes with different promoters or expression of completely new hybrid proteins with oncogenic potential. Also, it is traditionally believed that the integrated virus is in a latent state, allowing for continuous expression of oncogenes or downregulation of tumor suppressor genes without having cell death from productive or lytic infection. Nucleotide sequence analysis at 5 distinct loci across the 14-kilobase (kb) genome of more than 60 HHV-8 samples from KS and PEL tumors from North America, Africa, the Middle East, Asia, and the Pacific have revealed that they cluster into 4 major subtypes (A, B, C, and D). These can be further differentiated into 13 distinctive variants or clades. The B subtype, found in Africa, is the original. It is hypothesized that the evolution of 4 distinct strains, each concentrated in different locales, correlates with models describing human migration out of Africa in 3 distinct waves.7 The strong association be-

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tween locales and subtypes also indicates that HHV-8 is much more cryptic and much more difficult to transmit.23,41 The 140-kb genome of the virus, which is bound at each end by multiple 85% G ⫹ C terminal repeat units, has been sequenced in its entirety except for a 3-kb sequence near the right end of the genome. Among the 95 genes of HHV-8, nearly 25 are unique in the herpesvirinae.96 Those open reading frames (ORFs) not common to genes found in other herpesviruses are referred to by K number. Molecular studies have revealed an impressive armament of viral oncogenes within the HHV-8 genome. Paradoxically, most of these genes are not expressed in the latent state.97 This is a somewhat poorly understood phenomenon. Several of the genes believed to be most important in the oncogenicity of HHV-8 (particularly ORF 71, ORF 72, and ORF 73) are reviewed in the following sections. These 3 viral oncogenes are selectively discussed because they are the ones found to be consistently expressed in the latent state of HHV-8 infection.97 Lastly, the relevance of viral IL-6 will be discussed. Although this gene is expressed in the lytic cycle, investigators believe it may be significant in a paracrine fashion (Fig 10).55,58,59,98 Open reading frame 71 ORF 71 encodes the viral homologue to cellular Fas-ligand–interleukin 2– converting enzyme inhibitor protein (FLIP). Proteins from this class can inhibit Fas-mediated apoptosis. Normally, when the CD95 or Fas-ligand is activated by natural killer and other effector cells, signal transduction is mediated through the Fas-associated death domain protein (FADD). This protein subsequently activates death effector domains of the FLICE protease, also known as caspase-8. This activates cysteine proteases that are responsible for activating the apoptosis cascade. Viral FLIP has sequence homology, with both FADD and FLICE competing for the activators of these proteins.97,99 Viral FLIP is among the proteins highly expressed in the latent state of HHV-8 infection. Excessive expression of this protein could be an obvious contributing factor to cell transformation. Open reading frame 72 ORF 72 is a viral cyclin, a virus-encoded homologue of cellular cyclins. Among cellular cyclins, HHV-8 – encoded viral cyclin (v-cyclin) shares the greatest degree of homology with cyclin D2.96,99 Normally, cyclin D2 associates with cyclin-dependent kinase 6 (CDK6) and has weaker associations with other CDKs. The cyclin D2-CDK6 complex has the responsibility of phosphorylating retinoblastoma protein. This causes retinoblastoma protein to re-

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Fig 10. Events in HHV-8 cell transformation.

lease E2F, which activates the S-phase genes and allows for progression of the cell cycle from the G1 phase to the S phase. The complex formed between v-cyclin and CDK6 is immune to the CDKs, p16, p21, and p27, which normally inhibit the cyclin D2– CDK6 complex.99-101 This could also lead to unregulated progression of the cell cycle and cell transformation and might contribute to KS formation. Open reading frame 73 ORF 73 is latency-associated nuclear antigen (LANA). LANA may contribute to HHV-8-induced cell transformation by two distinct mechanisms. Cotter and Robertson102 propose a novel mechanism of latency. Analysis of LANA reveals several acidic and proline/glutamine–rich regions, as well as a zinc finger DNA-binding domain. LANA has been consistently detected in HHV-8 –infected cells. Through fluorescence in situ hybridization and immunofluorescence studies, LANA and HHV-8 DNA have been localized to the metaphase chromosome. Further studies have additionally indicated that LANA contains a preferential binding site for HHV-8 DNA in a

region known as Z6. Z6 resides within the first 34 kb at the left end of the viral genome. On the basis of these results, Cotter and Robertson102 hypothesize that LANA tethers the HHV-8 DNA to the metaphase chromosome, and by this means, maintains the latent state. Additional studies further characterizing these findings are warranted. Another important feature of LANA is its ability to interact with p53. It has been shown that LANA not only has the potential to inhibit the ability of p53 to induce cell death but also represses the transcriptional activity of the p53 gene.99,103 Open Reading Frame K2 (Viral IL-6) Unlike the other genes described previously, viral IL-6 (vIL-6) is primarily expressed during lytic infection and has not been found to be expressed in the latent state.98 However, this does not exclude its ability to contribute to the diseases in which HHV-8 is involved in a paracrine fashion because KS lesions consist primarily of latently infected cells, with small patches of lytic infection interspersed within the lesion.97 Another factor that led to some initial con-

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fusion as to the significance of vIL-6 is the fact that KS lesions do not seem to express IL-6 receptor␣.96,98 This is one of the two subunits that form the IL-6 receptor; the other one is gp 130. Through the IL-6 receptor, the JAK 1 and STAT 1/3 pathways are activated, which leads to increased cell division. Osborne, Moore, and Chang98 and Jenner and Boshoff99 suggest that vIL-6, unlike human IL-6, does not require the IL-6 receptor-␣ subunit and is capable of activating the JAK 1 and STAT 1/3 pathways with gp 130 alone. Variance in the expression of vIL-6 may also be one of the key factors explaining the production of different pathologic states from a single etiologic agent. One important question, unanswered in HHV-8 research, is how at least 3 distinct disease entities—KS, PEL, and MCD— could arise from a single virus. Infection of different cell types and expression of a different genetic program is one theory. Many investigators have reported on differential expression of vIL-6 as a significant factor.58,59 For example, it has been determined that vIL-6 is expressed in both PEL and MCD cells, but not in KS.55 The explanation for this differential expression has not yet been determined. However, it has been shown that in both KS and PEL, HHV-8 infection is primarily of the latent type. This was assessed by using a probe to nut-l, a well-known lytic transcript. Specifically, it was shown that both of these pathologic states consist of a vast majority of latently infected cells, with small dispersions of lytically infected cells.59 The differential expression of vIL-6 and possibly other genes may be due to the difference in cell type. Perhaps vIL-6 is part of the program for gene expression of HHV-8 in latently infected B cells but not endothelial cells. This is highly likely considering that IL-6 is an important B-cell growth and differentiation factor. MCD, on the other hand, shows only lytic infection, and the cell type infected includes both T and B cells, which explains why vIL-6 is so highly expressed in these lesions.55 HIV Tat protein The increased incidence of KS in patients with AIDS may be partially related to the HIV Tat protein. Studies have shown that the Tat protein promotes AIDS KS by at least two distinct mechanisms. First, heparin sulfate proteoglycans normally provide binding sites for ␤-fibroblast growth factor (␤-FGF). Tat competes for these sites, in turn increasing the concentration of free ␤-FGF. This is highly plausible because ␤-FGF is a well-described angiogenic factor.104-106 Second, HIV-1 Tat has been shown to activate HHV-8, thus increasing viral loads and leading to increased expression of a series of viral

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genes.107 These genes include vGCR (viral G coupled receptor), vBCL2, and vIRF1.108 Each of these genes has oncogenic potential. Specifically, vGCR promotes cell transformation and tumorigenesis of endothelial cells in vitro, as well as synthesis of vascular endothelial growth factor. The vBCL2 gene has anti-apoptotic activity, and vIRFI antagonizes interferon-mediated antiviral immunity and activates the c-myc oncogene. The HIV-1 Tat protein likely acts synergistically with HHV-8 through these mechanisms. Fc␥RIIIA The Fc␥RIIIA locus in humans displays genetic polymorphism. An association between specific alleles of this locus and development of KS has been observed.109 The genes code for an IgG receptor that attracts and binds phagocytes and other effector cells. The various alleles have different binding affinities. This could result in a variation in the cellular infiltration and cytokine environment where antibodies to HHV-8 are manifested. This variation may influence KS development, but a precise mechanism has not been described.

DISCUSSION Although KS was described by Kaposi in 1872, the disease became internationally recognized in the early 1980s with its high affliction rate in homosexual men with AIDS. At the time, more than 40% of homosexuals with AIDS had KS, whereas less than 5% of other patients with AIDS had KS. The epidemiology strongly suggested an infectious agent. Subsequent studies have linked KS with particular sexual practices, quantity of sexual partners, presence of other sexually transmitted diseases, and most recently the FC␥RIIIA genotype. In 1994, Chang et al3 made the discovery of HHV-8 using a novel method that confirmed the suspicions of clinicians and epidemiologists for decades. The virus was quickly characterized and found to share the greatest homology with gammaherpesviruses, a group known for its tropism and ability to maintain latency in lymphocytes. PCR and serologic evidence of HHV-8 has consistently been found in KS and several other entities. KS is commonly seen in 4 clinical variants: classical, epidemic, endemic, and iatrogenic; and all types have been directly linked to HHV-8.110 Most studies claim 90% to 100% prevalence of HHV-8 in all variants of KS. Furthermore, both in vitro and in vivo models have successfully implicated HHV-8 in KS formation. PEL and MCD are two other diseases that have also been strongly associated with HHV-8. Both AIDS and non–AIDS-related PEL are thought to be manifestations of HHV-8 with a prevalence of this

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virus equal to that in KS. However, although all cases of AIDS-related MCD have been linked to HHV-8, only half of the cases of non–AIDS-related MCD have either PCR or serologic evidence of HHV-8. There is currently no explanation for this finding. Many other diseases have also been examined for the presence of HHV-8, some with controversial findings.111-130 Several investigators have detected the presence of HHV-8 in the dendritic cells of MM; however, others have not been able to replicate this finding. Additionally, results of serologic studies have consistently been negative for HHV-8 in patients with MM. Low copy number and hypogammaglobulinemia have been proposed as an explanation for the negative PCR and serology test results, respectively.131,132 In other lesions, the findings have consistently been negative. An extensive number of epithelial and vascular lesions, as well as an extensive list of other diseases, have been examined for the presence of HHV-8. The overwhelming majority of evidence precludes a role for HHV-8 in these processes. Although angiolymphoid hyperplasia with eosinophilia may be one exception, the current data are not sufficient. HHV-8 has the potential for malignant transformation. Genetic sequencing of HHV-8 has revealed a multitude of cellular derived oncogenes. Studies have shown that most of these genes are expressed in the lytic and not the latent state of HHV-8 infection. However, KS predominantly consists of latently infected cells with interspersed lytically infected cells. FLIP protein, LANA, and v-cyclin are 3 viral oncogenes known to be extensively expressed in the latent state of infection. These genes are believed to be critical transforming factors of HHV-8. Conversely, vIL-6, another HHV-8 oncogene, is expressed in the lytic state of infection in KS. However, PEL and MCD have been found to be associated with high levels of this protein. Differential expression of vIL-6 and cell type infected are most likely responsible for the ability of HHV-8 to cause 3 distinct pathologic entities. The HIV virus may act synergistically with HHV-8 in AIDS-KS formation. KS is much more common in patients with AIDS. The HIV Tat protein has the ability to mobilize ␤-FGF by competing for binding sites on heparin sulfate proteoglycans. ␤-FGF is a strong angiogenic factor and probably contributes to KS formation in patients with AIDS. HIV Tat is also a likely transactivator of several HHV-8 oncogenes including vGCR, vBCL2, and VIRF1. Lastly, FC␥RIIIA, an immunoglobulin receptor for IgG, has been shown to influence susceptibility to KS formation. The allele at this locus has the potential to

determine the inflammatory infiltrate at the site of HHV-8 infection. Epidemiologic and molecular studies of KS and HHV-8 can significantly benefit public health and broaden our understanding of viral oncology. As we continue to gain a better understanding of the various sexual and nonsexual means by which HHV-8 is transmitted, greater measures can be taken to limit its spread. Data regarding the benefits of various PIs and how to optimize treatment are also significant. Lastly, several unique mechanisms may be involved in HHV-8 cell transformation, including a novel method of viral latency, synergy with HIV, and paracrine stimulation by oncogenes from cells with HHV-8 lytic infection. A better understanding of these mechanisms may help establish a more ideal model for viral oncogenesis. REFERENCES 1. Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med 2000;342: 1027-38. 2. Rappersberger K, Stingl G, Wolff K. Kaposi’s sarcoma. In: Freedberg I, Eisen A, Wolff K, Austen K, et al, editors. Fitzpatrick’s dermatology in general medicine. Vol 1. 5th ed. New York: McGraw-Hill; 1999. p. 1195-204. 3. Chang Y, Cesarman E, Pessin MS, et al. Identification of new herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 1994;266:1865-9. 4. Ensoli B, Sturzl M, Monini P. Reactivation and role of HHV-8 in Kaposi’s sarcoma initiation. Adv Cancer Res 2001;81:161-200. 5. Sturzl M, Zietz C, Monini P, Ensoli B. Human herpesvirus-8 and Kaposi sarcoma: relationship with the multistep concept of tumorigenesis. Adv Cancer Res 2001;81:125-59. 6. McGeoch D, Davison A. The descent of human herpesvirus 8. Semin Cancer Biol 1999;9:201-9. 7. Hayward G. KSHV strains: the origins and global spread of the virus. Semin Cancer Biol 1999;9:187-99. 8. Chatlynne L, Ablashi D. Seroepidemiology of Kaposi’s sarcoma-associated herpesvirus (KSHV). Semin Cancer Biol 1999;9: 175-85. 9. Lennette ET, Blackbourn DJ, Levy JA. Antibodies to human herpesvirus 8 in the general population and in Kaposi’s sarcoma patients. Lancet 1996;348:858-61. 10. Whitby D, Luppi M, Barozzi P, Boshoff C, Weiss RA, Torelli G. Human herpesvirus 8 in blood donors and lymphoma patients from different regions of Italy. J Natl Cancer Inst 1998;90:395-7. 11. Biggar RJ, Whitby D, Marshall V, Linhares AC, Black F. Human herpesvirus 8 in Brazilian Amerindians: a hyperendemic population with a new subtype. J Infect Dis 2000;181:1562-8. 12. Rabkin CS, Schulz TF, Whitby D, Lennette ET, Magpantay LI, Chatlynne L, et al. Interassay correlation of human herpesvirus 8 serologic tests. HHV-8 Interlaboratory Collaborative Group. J Infect Dis 1998;l78:304-9. 13. Grulich AE, Olsen SJ, Luo K, Hendry O, Cunningham P, Cooper DA, et al. Kaposi’s sarcoma-associated herpesvirus: a sexually transmissible infection? J Acquir Immune Defic Syndr Hum Retrovirol 1999;20:387-93. 14. Hermans P. Epidemiology, etiology and pathogenesis, clinical presentations and therapeutic approaches in Kaposi’s sarcoma: 15-year lessons from AIDS. Biomed Pharmacother 1998;52: 440-6. 15. Dukers N, Renwick N, Prins M, Geskus R, Schulz T, Weverling GJ,

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