KAPOSI'S SARCOMA AND HUMAN HERPESVIRUS-8

EMERGING INFECTIOUS DISEASES

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KAPOSI’S SARCOMA AND HUMAN HERPESVIRUS-8 Ruth M. Greenblatt, MD

After years of suspicion that Kaposi’s sarcoma (KS) is caused by an infectious agent,lZ6in 1994 Chang and associatesz4reported identification of a herpesvirus-like DNA sequence from tissue recovered from KS lesions of an AIDS patient. The sequences resembled, but were distinct from, those of herpesviruses of the family Gammaherpesvirinae: Epstein-Barr virus (EBV) and herpesvirus saimiri, a pathogen of nonhuman primates. Thus, the KS-associated virus appeared to be a new herpesvirus. In addition, the new virus, identified as KSassociated herpesvirus (KSHV) or, the more frequently used name, human herpesvirus type 8 (HHV-8):52 appears to represent a transmissible causal agent for several malignancies. KS is the most common malignancy in patients with HIV infection, reported as the initial AIDS-defining condition in over 20% of patients. The presence of HHV-8 infection has now been found in over 95%of KS tumors, supporting evidence that HHV-8 has a causal role in the development of KS. The discovery has contributed new avenues for understanding the epidemiology of KS and related conditions, the molecular basis of viral-induced carcinogenesis, and identification of novel therapeutic and prophylactic approaches for KS. KAPOSI’S SARCOMA Clinical and Pathologic Characteristics

Kaposi’s sarcoma (KS) is found in four distinct settings: (1) in its classic form, KS has long occurred as a rare condition seen most frequently among Support provided by the Wellman Family Fund and the UCSF AIDS Clinical Research Center

From the Infectious Diseases Division, University of California San Francisco, San Francisco, California

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA

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elderly men in Mediterranean c o ~ n t r i e s ' ~( 2~); a long-described endemic form affecting children and adults occurs in tropical Africa; (3) a more recently recognized variant, the so-called "iatrogenic" form of KS, that occurs as a relatively common tumor in persons with medically-induced immunosuppression, such as organ transplant recipientsl0'; and (4) the form linked with the AIDS epidemic, KS occurs as a common malignancy occurring among persons with HIV i n f e c t i ~ n . ' ~ ~ Moritz Kaposi first described KS (the classic form) in 1872 as a rare skin tumor seen primarily in elderly men of Mediterranean or Ashkenazi Jewish origin.MThe disease typically involves the lower limbs, progresses slowly, and patients often succumb to diseases other than KS.132The endemic or African form was recognized in the early part of this century, and is confined to equatorial areas where until the AIDS era it accounted for up to 10% of all malignancies.gSIn adults, endemic-form KS has a varied course, ranging from relatively mild disease (similar to the classic form) to locally aggressive disease.'21 The iatrogenic form of KS tends to be an aggressive illness with rapid dissemination unless immune suppressive therapies are discontinued.''2 AIDS KS also has a variable course, including aggressive disease with rapid dissemination to multiple cutaneous lesions, lymph nodes, and eventually, organ involvement.30 AIDS KS lesions are often elliptic, follow linear skin tension lines, and may be symmetrically d i s t r i b ~ t e d .They ~ ~ may appear anywhere on the body, but tend to be concentrated on the lower extremities, genitalia, and most distressingly, on the face. Early lesions appear as faint red-violet or brown macules and can be mistaken for other more benign lesions.3a AIDS KS lesions are most commonly identified as papules of varied color and size, ranging from several millimeters to centimeters. Lesions, particularly those of the lower extremity, can become exophytic or plaque-like, and can produce ulceration of the overlying skin.30Lymphedema is common and can be out of proportion to the extent of skin and lymphatic iqvolvement, perhaps due to cytokine a~tivity.~" Spread to the oral cavity is common, and oral lesions may be the first manifestations of disease. Lymph nodes are involved in one third of cases that present at autopsy.6O Gastrointestinal (GI) and pulmonary involvement is also common in late disease,6O when extensive cutaneous disease is already present, and accounts for significant morbidity and m ~ r t a l i t y GI . ~ ~KS is easily identified after visualization via fiberoptic endoscopy as hemorrhagic nodules that vary in size and can involve any portion of the GI tract. Occult blood is often detectable in Pulmonary KS often presents with dyspnea, fever, and cough. Nodular parenchymal densities or pleural effusions are the most characteristic radiographic appearance of pulmonary but often radiographs demonstrate bilateral perihilar infiltrates;la6thus, the symptoms and radiographic appearance The diagnosis is of pulmonary KS are not easily distinguished from infecti01-1.~~ frequently made p o s t m ~ r t e m Computerized .~~ tomographic appearance can be somewhat more specific, including abnormal hilar densities that extend into parenchyma along perivascular and peribronchial pathways,'06but the radiologic diagnosis is often Bronchoscopic diagnosis is relatively simple if endobronchial lesions are identified5'; if not, histologic evaluation of blind small tissue samples is diagnostic in only about 10% of cases.'47 Although KS is less prevalent in women with AIDS than in men, when it does occur it has similar manifestations and prognosis.79Lesions often involve the as in men, and may involve the breast.'" Histologically, the KS forms are indi~tinguishab1e.l~~ Lesional tissue is sorted into three categories based on the proportion of spindle cells, fibrosis, and nuclear pleomorphism.

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The predominant patterns include a mixed cell pattern with equal proportions of spindle cells, vascular clefts, and well-formed capillaries; a mononuclear pattern with proliferation of one cell type, most often spindle cells; and an anaplastic form with pronounced cellular pleomorphism and numerous mitoS ~ S Clinical . ~ ~ staging systems have been developed based on the clinical appearance of the predominant lesions, clinical aggressiveness, and presence of bone inv~lvement.’~~ Krigel” proposed a staging system based on the characteristics of cutaneous lesions and the extent of involvement at presentation; stage is predictive of survival time.96Staging systems for AIDS KS include the level of HIV morbidity features as well as measures of the extent of KS and also predict survival.76Survival is best predicted by absolute CD4 cell count, hematocrit, number of lesions, and body mass index at diagn0sis.9~ The derivation of KS and whether it is truly a malignancy has been controversial for many years.48Vascular endothelial cells are conjectured to be the cellular origin of spindle cells in KS because of the angiocentri: nature of the lesions and the presence of extravasated red blood cells, ultrastructural appearance, and the cellular expression of various endothelial markers.4xDermal dendrocytes are also present in KS lesions but have now been excluded as the origin of spindle cellsj8 Spindle-like cells can be recovered from the peripheral blood of HIV-infected and uninfected persons. Greater numbers of these cells circulate in AIDS KS patients and in HIV-infected homosexual men, suggesting that the multifocal nature of KS lesions may be due to hematologic spread of the disease.I7 The finding that spindle cells in multiple KS lesions are monoclonal provides additional support for the hypothesis that KS is a malignant condition. Epidemiology

Until the AIDS epidemic, KS was a rare tumor in most of the world. The age-adjusted incidence in the United States during the years 1973 to 1981 was 0.29 cases per 100,000 men and 0.07 cases per 100,000 women.1zFifteen percent to 20% of homosexual men with AIDS have presented with KS.2zSince 1981, at least 98% of KS reported in the United States has been AIDS related.” In Greece, a country in which classic KS was prevalent prior to HIV, the introduction of HIV has been associated with an increasing incidence of KS, occurrence of the disease in younger individuals, and increases in the male-to-female ratio of cases.14o Epidemiology of AIDS Kaposi’s Sarcoma

Worldwide, the HIV epidemic is associated with dramatically increased incidence rates of KS. In 1990, Beral and colleaguesyanalyzed the factors associated with KS among the first 91,000 AIDS cases reported in the United States. They found that the risk of KS was at least 20,000 times greater among AIDS patients than the general population and 300 times greater among AIDS patients than other immunosuppressed populations. Biggar and ass~ciates’~ determined that the relative risk of KS among homosexual and bisexual men was an astonishingly high value of 106,000 when compared with the non-AIDS population and 13,000 for other men with AIDS when they are compared with the nonAIDS pop~lation.‘~ KS and non-Hodgkin’s lymphoma account for almost all excess cases of cancer attributed to AIDS1I5;KS occurs more frequently than non-Hodgkin’s lyrnph~ma.”~

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Kaposi’s sarcoma is most prevalent among men who have sex with men (21% of homosexual men had KS), regardless of intravenous drug use, compared with other HIV exposure groups (prevalence of KS varies from lY0-6~/~)? Men with hemophilia and women who acquired HIV by heterosexual contact have the lowest incidence of KS.9 Men with AIDS are much more likely to develop KS than women with AIDS, although often these differences disappear when homosexual men are excluded from analyses.I6Several studies of women with AIDS have identified an association between KS and a sexual mode of HIV transmission as well as prior sexual contact with bisexual men9 Prostitution has also been identified as a risk factor for KS among female AIDS patients? Thus, sexual exposure, with highest rates of transmission for male-to-male sex, could explain the predominance of cases among men. An alternative explanation for the skewed gender distribution of KS cases is a possible protective effect of female sex hormones”; however, the finding of lower gonadotropin levels in KS patients compared with other patients is confounded by the effects of wasting. Although human chorionic gonadotropin has in vitro inhibitory effects on KS cells, the incidence of KS does not appear to be diminished by pregnancy, also arguing against a significant protective When KS occurs in women, it is often the first indication of HIV infe~tion.~ KS has been found to be associated with high-risk sexual behavior, particularly among men, in many studies. Michalzek and colleaguesy1analyzed the occurrence of malignancy among 16,000 persons reported with syphilis. In this study, KS had a very high standardized incidence ratio among men with syphilis (2,000), but not women, whose value was 0.91Grulich and colleagues4yreported a study of homosexual men residing in Australia; the occurrence of KS was associated with a previous history of sexually transmitted diseases and insertive oral-anal contact with casual sexual partners.4yThe Multicenter AIDS Cohort Study, a longitudinal study of HIV in a well-characterized group of homosexual men, identified a dose-response relation between number of sexual partners or history of prior sexually transmitted diseases and the occurrence of K S 6 Thus, the majority of epidemiologic findings support the notion that KS is caused by a sexually transmissible agent: or more speculatively, an exposure to a toxic substance used during sexual activity, such as inhaled nitrites54;however, because HIV is itself sexually transmitted, the relationship between KS, HIV, and other factors that are linked with sexual behavior could be highly confounded and mi~1eading.l~~ In developed nations, the proportion of AIDS cases that present with KS has steadily declined since the onset of the epidemic,I3although data from men with known dates of seroconversion indicate the decline in KS cases has leveled off during the late 1 9 9 0 ~ .Several ’ ~ ~ explanations have been put forward for these trends: (1) increasing proportion of AIDS cases occur in population groups that traditionally have low incidence rates of KS (women, injection drug users, and persons who reside away from the high KS incidence areas of the coastal United States and E ~ r o p e ) (2) ~ ; increases in AIDS cases among persons of color who may be less likely to be diagnosed with early KS3; (3) the tendency for KS to occur earlier in the course of HIV infection (shorter latency period) than other AIDS-defining conditions would result in a higher proportion of AIDS diagnoses early in the epidemicI3; (4) changes in the case definition of AIDS to include CD4 cell depletion would tend to ”dilute” the proportion of KS index diagnoses; (5) reduction in the incidence of behaviors that confer risk of KS143;and (6) reduced virulence of a KS ofa actor.^^ It is likely that several of the explanations may contribute to the changing incidence of KS in AIDS. Changes in the afflicted population cannot explain all

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of the decrease in KS cases. The incidence of KS among homosexual and bisexual men with HIV infection fell from the highest rates very early in the AIDS epidemic (79% of AIDS cases) to much lower incidence rates (25%) within the initial 10 years of the epidemic.83Survival after a diagnosis of KS is longer than almost all other AIDS-defining conditions, a finding that supports the concept that KS is an early-occurring index c0ndition.9~ Non-AIDS Kaposi's Sarcoma

In endemic KS, the form common in tropical Africa, disease is reported equally among men and women, and occurs among children. AIDS-associated KS is rare among children residing in developed countries,8Rand when it does occur, it is more common among children born to mothers who were also at higher risk for KS (had homosexual or bisexual male partners). Iatrogenic immunosuppression is an increasingly common risk factor for KS and other soft-tissue sarcomas. KS is relatively common among organ allograft recipients; 0.6% of renal allograft recipients develop KS, usually within 5 years of tran~plantation.~~ Comparable KS incidence rates among cardiac and hepatic transplant recipients have been reported.25Approximately 3% of tumors that develop in organ transplant recipients and 10% of tumors occurring in recipients of cyclosporine immunosuppression develop KS.llz Overall, renal transplant recipients are at 400- to 500-fold greater risk of developing KS when compared with controls of the same ethnic although breast, colon, prostate, and lung cancer are not increased in incidence among transplant recipients."' In renal transplant recipients the incidence of KS is also correlated with the level of immune suppression; higher doses of cyclosporine A or number of episodes of rejection treated with methylprednisolone pulses is associated with occurrence of the turnor.'O' In transplant recipients the KS lesions are most commonly cutaneous, but may primarily involve the allografted organF5 The incidence of KS in transplant recipients varies with region of origin, with higher rates occurring among ArabiE, Jewish, African, or Mediterranean ancestry.13 In the transplant recipient population, KS tends to occur more frequently among women than in other high-risk groups, with a male-to-female ratio of 2.9:l versus the 9:l or 151 ratio reported in the general population."' KS is also one of the earliest tumors to occur in organ transplant recipients, occurring at an average of 22 months after transplantation, followed by non-Hodgkin's lymphomas at 32 months, and epithelial malignancies at 69 months."' Onset of KS occurs even earlier among persons receiving cyclosporine KS also can occur among persons who receive immunosuppressive therapy for reasons other than organ transplant; reports include the appearance of KS after relatively brief exposure to immunosuppressive therapy.'41 The clinical course of immune suppression-associated KS can be very aggressive, with a mortality rate of 34% within 3 years of diagnosis.38Withdrawal of immunosuppressive therapy can result in disappearance of the malignan~y,'~~ but not always'41; recurrences of KS can occur with the resumption of immunosuppressive therapy."' Pretransplant KS is also a risk factor for recurrent diseaseA6

Clues to a Viral Origin Many epidemiologic findings support the theory that KS is caused by an infectious agent. In AIDS patients the KS causal agent appears to be associated

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with, and yet functionally independent of, HIV. The association between KS and HIV is much stronger than the association between other malignancies that infectious agents are purported to cause, such as hepatoma and hepatitis B virus or cervical cancer and human papill~maviruses.'~~ HIV and HIV products have not been consistently identified in KS tissue, and KS occurs in HIV-uninfected individuals; thus, it appears unlikely that HIV is the causal agent for the development of KS.'O HIV may potentiate a number of factors that promote the development of KS, such as CD4 cell depletion, alterations in cytokine release, and production of mitogens that influence KS cell activity. In AIDS the occurrence of KS is linked with depletion of CD4-positive lymphocytes (CD4 cells) that function to recognize foreign antigens via HLA class 2 proteins?2 HIV-mediated depletion of CD4 cells could result in increased activity of a KS causal agent, and thus increase the likelihood that KS will occur. KS lesions are often noted to progress during AIDS-related opportunistic infections (OIs), perhaps due to the influence of increased levels of interleukin (IL-1, IL-6) and tumor necrosis factor (TNF-a) associated with O I S .HIV-infected ~~ cells have been demonstrated to produce TNF, IL-1, and IL-6.93In addition, administration of granulocyte/macrophage-colony stimulating factor (GM-CSF) has been observed to be associated with an increase in the size of KS lesions.55 The finding that KS lesions include several cell lines, and not a single clone or specific cytogenetic mutations (as seen in most cancers) along with the inflammatory nature of many of the cellular constituents, supports the concept that inflammatory processes are important in the development of KS lesions.34TNF, IL-1, IL-6, and oncostatin M can trigger proliferation of KS cells in culture and induce normal cells to morphologically change to resemble KS spindle ~ells.9~ Coadministration of glucocorticoids has been demonstrated to enhance the effect of oncostatin M on the proliferation of KS cells in culture.50Overproduction of basic fibroblast growth factor (b-FGF) and IL-6 has been demonstrated in AIDS patients several months before the Occurrence of KS.78 Similar findings have been noted in tissues from persons with the endemic form of KS.6' Thus, several investigators hypothesized that KS may be a disease that results largely from the disregulation of cytokines and cellular growth factors.82KS cells themselves release cytokines, including IL-1, GM-CSF, and IL-6.34Other substances that are produced by KS cells, such as b-FGF, KS-fibroblast growth factor (K-FGF), promote angiogenesis, which may in part cause the highly vascular nature of KS lesions.34b-FGF and IL-1 also stimulate production of macrophage CSF from marrow cells and other cytokines, and may promote an escalating positive feedback loop for the production of inflammatory cytokines' and drive progression of KS lesions and HIV disease itself.65 In addition to stimulating release of cytokines, HIV may also stimulate proliferation of KS cells via its gene product HIV tat, a small polypeptide that could function as a mitogen. HIV tat influences HIV gene expression, and small quantities are released from infected cells. HIV tat binds to KS cells and can promote cell growth and surface adhesion.I8HIV tat also promotes the secretion of IL-6 by KS cells.123HIV tat appears to induce angiogenesis in AIDS KS spindle cell~,3~, 36 and synergy with b-FGF may occur. Tat may also act synergistically with TNF to activate endothelial ~ells.5~ As described in preceding sections, the occurrence of iatrogenic KS closely follows intensity of immunosuppression.'01 All of the findings more strongly support the theory that KS is caused by an infectious agent rather than a toxin, such as amyl nitrite. Cytomegalovirus, Mycoplasma penetrans, hepatitis B virus, Epstein-Barr virus (EBV), human papillomaviruses, Chlamydia trackomatis, BK virus infection, and HHV-6 have each been considered as possible etiologic agents.loo

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HUMAN HERPESVIRUS-8 In 1994, Chang" and Moorelo2reported the identification of herpes-like DNA sequences in KS tissues from patients with AIDS using a powerful new technique called representational diflerence analysis. The technique permitted the detection of DNA sequences that are present in KS tissue but absent or present in low copy number in nondiseased ti~sue.8~ Several of the sequences were partially homologous to gene segments of y-herpesvirinae, herpesvirus saimiri, and EBV." Most importantly, the sequences were not identified in tissues from normal hosts, lymphoma and lymph node tissue, EBV-infected peripheral lymphocytes, DNA extracted from vascular tumors, and tissues with AIDS 01s. Fifteen percent of non-KS tissue DNA from AIDS patients contained the herpesvirus-like DNA." Chang's report was soon followed by other descriptions of a novel herpesvirus associated with KS, now known as KSHV or, more commonly, human herpesvirus4 (HHV-8). Among the 100 or so herpesviruses that have been identified in nature, 8 have now been isolated from humans, including a-herpesvirinae (herpes simplex viruses 1 and 2 and varicella-zoster virus), @-herpesvirinae(cytomegalovirus, human herpesviruses 6 and 7), and y-herpesvirinae (EBV, HHV-S)."* ?-Herpesviruses are DNA viruses that establish latent infection in lymphocytes and are associated with cell pr~liferation~~ and with development of malignancies. EBV is associated with B lymphoproliferative disease in immune compromised persons and persons with Burkitt's lymphoma, Hodgkin's disease, unusual T-cell lymphomas, and nasopharyngeal car~inoma.6~ Production of infectious progeny is associated with cellular lysis and death. In latent infection the viral genome exists as an episome, and only a portion of viral genes are expressed.90Various stimuli can reactivate the virus into a lytic stage, leading to clinical relapses or recurrent disease. Although HHV-8 was first identified in 1994, the evidence, based on DNA divergence studies in this and other human herpesviruses, suggests that HHV8 is an ancient and well-established human virus, although infrequent in its occurrence and geographically isolated until very recently.148 Monoclonal expansion of viral DNA is present in KS lesions.'2oHHV-8 genes have been found to code for a thymidylate synthetase, a dihydrofolate reductase, four novel cytokine genes (including viral products homologous to cellular IL-6, complement binding proteins, macrophage inflammatory proteins [MIP-11 (Y and MIP-1 @, and a less homologous brain creatine kinase [BCKI-like product), interferon regulatory factors, a neural cell adhesion molecule-like adhesin, a protein analogous to a cellular D-type cyclin, a protein similar to domains of the PHD/leukemiaassociated protein, and a protein homologous to human IL-8 receptor (KSHV Gprotein-coupled receptor).lD2 Other sections of the genome code for nuclear RNA segments that associate with cellular ribonucleoprotein complexes.149 Transfection of newborn rat kidney (NRK) cells in culture with G-protein-coupled receptor stimulates proliferation; thus the receptor is a candidate viral ~ n c o g e n e . ~ Cellular cyclins regulate the cell cycle; thus HHV-8 encodes for several products that could mimic cytokine pathways and may function to induce potentiate malignant cellular transformation (this is consistent with the theory that the virus is a cancer causal agent). In addition, MIP-1 proteins may influence cytokine homeostasis and could alter HIV disease progression.108 Human Herpesvirus-8 and Cancer Subsequent to identification of HHV-8 by Chang, many published reports of the high prevalence of HHV-8 DNA sequences in KS tissue specimens have

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added support for an association between the newly described virus and KS (AIDS-associated forms as well as the others) and the lack of a similar association One study of KS cases in central Africa between KS and other herpesviru~es.~~ found that DNA from HHV-8 and EBV were both highly prevalent in lesional ~amp1es.l~~ In addition, the associatior. between HHV-8 and KS appears to be relatively specific. Similar associations between the HHV-8 and many other conditions that do not fit the epidemiologic pattern of KS have been looked for and not found,20with few exceptions116;these are likely due to differences in PCR technique. HHV-8 DNA has been detected in KS lesional tissue from various body sites, such as oral and in the respiratory tract of immune compromised patients with pulmonary KSZ1HHV-8 sequences have been detected in sensory ganglia of KS patients, an observation that could explain the tendency for KS to assume a symmetrical distribution.26HHV-8 infection of peripheral blood mononuclear cells (PBMC) appears to precede onset of KS, at least in some Smith and Chandran discovered high levels of serum antibodies to both lytic and latent HHV-8 antigens in patients with KS but not in HIV-infected patients without KS.Iz8 Most recently, Foreman, Nabel and colleagues were able to propagate HHV-8 in a kidney epithelial cell line after coculture with KS lesion cells.4oSeveral investigators have not succeeded in identifying HHV-8 DNA sequences in KS spindle cells: raising the possibility that HHV-8 is more a passenger virus than a causal agent.lz7More recently, Staskus and Haase were able to consistently identify KSHV RNA segments in KS spindle cells but not in other angiomatous tissue, and infrequently in other tumor Studies of macaques with the simian acquired immunodeficiency syndrome and simian retroperitoneal fibromatosis, a condition which histologically resembles KS, has revealed new y-herpesviruses with DNA sequence segments that are closely related to HHV-8, a finding that strongly supports a causal role for the new herpesviruse~."~ In humans it appears that most KS cells are latently infected with HHV-8, and lytic replication occurs in a small subpopulation of cells,'50 HHV-8 DNA sequences have been identified in several other cancers, most of which are associated with immune compromise. Because lymphoid cancer is noted in KS patients2 and because the risk of malignant lymphoma is increased in AIDS patients, Cesarman and colleagues examined DNA extracted from 193 lymphoma tissue samples.23HHV-8 DNA was found in eight body-cavity-based lymphomas (BCBL) in HIV-infected persons; tissue from other lymphomas, including samples from HIV-infected and uninfected persons, had no detectable HHV-8. HHV-8 DNA has subsequently been identified in other studies of BCBL tissue in HIV-infected and uninfected patients.44The HHV-%positive BCBL appears to have unique clinical, pathologic and immunologic characteristics (predominantly occurs in men, localizes to a body cavity, progresses rapidly, has morphology that bridges large-cell immunoblastic and anaplastic types, and is monoclonal in nature, having unique genetic rearrangements and antigenic composition) and may represent a distinct clinicopathologic entity." Although most HHV-8 associated BCBL present as malignant effusion of a body cavity, HHV-8 DNA has been detected in tissue derived from lymphoma of the bowel that subsequently produced malignant effusion and otherwise fit the characteristics of the HHV-8-associated BCBL.z9HHV-8 DNA has also been identified in normal-appearing colon and duodenum from HIV-infected individuals.138The two findings of HHV-8 in the GI tract support the concept that the virus may be transmitted via fecal-oral sexual contact. In some of the studies BCBL cells also demonstrated EBV DNA, supporting the hypothesis that the two viruses act in conjunction to induce malignant transformati~n.~~ HHV-8 sequences were

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much more numerous in the BCBL than in KS a finding that suggests the virus plays a pathogenic role in BCBLj2 HHV-8 DNA sequences have also been identified in PBMC and lesional tissue from patients afflicted with multicentric Castleman's disease (MCD), an angiofollicular hyperplasia associated with fever, adenopathy, and splenomegaly commonly reported in patients with AIDS and KS.33Although HHV-8 appears to be universally present in MCD in AIDS patients, far fewer MCD patients without HIV infection appear to have HHV-8 infection.13"Exacerbations of MCD symptoms were associated with increases of the quantity of HHV-8 DNA in PBMCs of three HIV-infected patients studied by Grandadam and c0lleagues.4~ HHV-8 DNA sequences have also been detected in angiosarcoma and angiolymphoid hyperplasia but not in B-cell non-Hodgkin's lymphoma or primary central nervous system Epidemiology of Human Herpesvirus-8 Infection

DNA sequencing of the HHV-8 genome reveals three distinct and narrow subtypes, denoted A, B, and C. B and C strains appear to predominate in KS patients from Africa, type A predominates in the classic Mediterranean form of KS, and all three strains occur in the United States.14R Interestingly, many samples from the eastern United States are type A with nearly identical DNA sequences, including regions that are not conserved biologically. This raises the possibility that most of the HHV-8 genomes occurring in United States AIDS patients derive from a single ~ubstrain,'~~ a finding consistent with a common source of infection. DNA detection techniques, such as PCR, are of limited value in the description of the epidemiology of HHV-8 and studies of viral transmission because infected tissue must be directly sampled and the technique is cumbersome and sensitive to laboratory error.28Production of a highly specific serologic assay is made challenging by th6 potential for cross-reactivity between EBV and HHV-8 antigens and antibody responses. Indirect immunofluorescence assays have been developed for the detection of lytic and latent HHV-8 antigens, and are currently being employed to define the prevalence and incidence of infection in many population groups.68 Using an EBV-uninfected BCBL cell line developed by Ganem and colLennette, Blackbourn, and Levy developed immunofluorescence assays for serum antibody to latent or lytic HHV-8 antigens? Antibodies to latent antigens were detected via characteristic binding of fluorescent mouseantihuman antibody to nuclear antigens of untreated BCBL cells. Antibodies to lytic antigens were detected via characteristic binding of fluorescent mouseantihuman antibody in cytoplasm of phorbol-ester- and IL-6-treated BCBL cells. Antibodies to latent antigens (latent antibody) was present in patients with KS, HIV infection, and residents of six African countries, but not among HIVuninfected residents of the United States, Haiti, the Dominican Republic and Guatemala, and various patient populations, including persons with EBV reactivation, hemophilia, and nasopharyngeal carcinoma. Antibody to lytic antigens (lytic antibody) was more prevalent than latent antibody; prevalence rates varied from 100% of African KS patients, 90% to 100% of male homosexual HIV patients, 23% of HIV-infected IDU, and 21% of HIV-infected women. The lytic antibody assay was 97% sensitive for KS. Lower prevalence rates among IDUs and hemophiliacs (23% and 15%, respectively) suggest that parenteral transmission of the virus is not common. As is true of many herpes simplex virus

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infections and chronic sexually transmitted diseases (STDs), prevalence rates tended to increase with age and peaked during years of greatest sexual activity. Among United States residents, 0% to 5% of children under the age of 2 years were HHV-8 lytic antibody-positive compared with 16% to 28% among adultsR1 Cross-reactivity with antibody to EBV antigens was not significant. Serological results corresponded to DNA PCR results on a subset of These findings support the theory that HHV-8 is sexually transmitted, perhaps via a fecal-oral route. Other serological prevalence studies also support a sexual mode of transmission. The Kedes study identified latent antibody in 80% of AIDS-KS patients, 30%of HIV-infected homosexual men, 2% to 4% of hemophiliacs and transfusion recipients, and 1% to 2% of healthy blood donors, using an indirect fluorescence antibody (IFA) technique.68In follow-up to that study, Kedes reported that 4% of HIV-infected women and 1%of HIV-uninfected high-risk women had serum antibody to latent antigen via IFA te~ting.6~ The results of these studies suggest that latent antibody may be more closely associated with risk of KS than lytic antibody. Conversely, lytic antibody may be a more sensitive indicator of exposure to HHV-8 than latent antibody. Smith and Chandran compared DNA PCR results from lesional and normal skin from HIV-infected patients with and without KS with PCR of PBMCs and IFA reactivity to serum latent and lytic antibodies. Eight of nine KS lesion, four of seven normal skin, and four of eight PBMC samples from KS patients had positive PCR results. All seven KS patient sera were positive for both latent and lytic antibodies. Only 2 of 18 PBMC samples from HIV-infected patients without KS had positive PCR results, although 6 of 18 serum samples were positive for both lytic and latent antibodies. Antibody titers for both lytic and latent antigens were much higher in serum from KS patients than the HIV-infected patients without KS.IZR If HHV-8 is sexually transmitted, it should be present in genital and perhaps oral and GI secretions. In 1996, Monini, Cassai, and colleagues reported the detection of HHV-8 DNA sequences in a high proportion of genital tract tissue and semen samples from Italian patients.99In blinded and unblinded analysis, 50% to 91%, respectively, of semen samples from men not known to have HIV infection or KS were found to have HHV-8 DNA sequences. Similarly, prevalence rates for HHV-8 DNA in prostatic and vulvar tissues were high (63%and 33%, respectively). Corbellino detected HHV-8 DNA in prostate tissue but not in the semen of Italian men with KS, and not in any tissue from men without KS.Z7 Tasaka studied prostate, vulvar, and cervical cancer patients from the United States and Italy and failed to detect HHV-8 DNA sequences in any.136 Huang performed DNA PCR studies of matched PBMC and semen specimens from AIDS KS patients and HIV-infected and uninfected homosexual men, and found 3 of 12 PBMC and 3 of 12 semen samples from AIDS KS patients were positive HHV-8 sequences,58but none of the specimens from men without AIDS KS were positive. In situ PCR was performed on some of the HHV-8-positive semen specimens; HHV-8 DNA was seen in spermatozoa and mononuclear Viviano, Romano, and others studied semen from HIV-infected and uninfected homosexual and heterosexual men with and without KS, and cervical swab specimens from HIV-uninfected women, and found HHV-8 DNA sequences in ejaculates from each of the groups of men studied and in none of the cervical samples144;however, Koelle, Corey, and associates did not identify HHV-8 DNA sequences in the semen of 12 AIDS KS patients and 10 HIVinfected men without KS.71Overall, current findings provide some support for the concept that HHV-8 is present in semen from AIDS KS patients and from an uncertain proportion of HIV-infected and uninfected men without KS. Lack

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of consistent detection of HHV-8 DNA in samples from healthy men could be due to a high rate of falsely positive PCR assays, the intermittent presence of the virus in detectable quantities, or a combination of factors. Nonetheless, it appears plausible that HHV-8 could be transmitted via sexual contact with infected ejaculate. Human herpesvirus-8 DNA sequences have also been detected in oral tissue and oral secretions. Di Alberti and associates identified a DNA segment specific to HHV-8 in 10 of 14 oral tissue samples taken from HIV-infected patients who did not appear to have KS. Similar segments were not detected in 20 HIVuninfected patient^.^' Koelle and Corey detected HHV-8 DNA sequences in 19 of 25 saliva specimens obtained from KS patients (including one HIV-uninfected man), 3 of 20 HIV-infected and KS-negative patients, and from 0 of 24 HIV- and KS-negative controls.71Application of DNase treatment to saliva specimens did not eliminate the sequences, indicating that at least some of the DNA was present within intact virions. This suggests that HHV-8 is replicated with the oropharynx or in tissues that drain into the oral cavity.71These studies indicate that HHV-8 may replicate in the oropharynx and could be transmitted via saliva contact in a manner analogous to EBV. KAPOSI’S SARCOMA IN CHILDREN Pediatric Kaposi’s Sarcoma in Developed Countries Kaposi’s sarcoma occurs rarely in children with AIDS in developed counAIDS KS is seen in children born to mothers in high-risk groups for KS (history of intimate contact with a bisexual male partner) or who acquired HIV infection postnatally via blood product administration.110 In the United States, black children were found to have nearly a three-fold excess of KS compared with white children. Excess cases were also identified in male adolescents who reported having sexual intercourse with men.lZ4 Kaposi’s Sarcoma in African Children Before the AIDS epidemic, KS was a rare tumor in African ~hi1dren.I~~ When it did occur, lymphatic involvement with an aggressive course was seen.lo9The incidence of childhood KS in Africa has increased markedly since the advent of AIDS.8 Ziegler and Katongole-Mbidde recently reported the results of medical record reviews on 100 childhood KS cases diagnosed between 1989 and 1994 at the Uganda Cancer 1n~titute.l~~ The median age of onset of KS was 33 months. Eighty-two percent of cases initially presented with head and neck lesions. Of the 63 children who had received HIV serologic tests, 78% were HIV seropositive; 69% of the 35 mothers who were tested were HIV seropositive. Eight of eight children’s KS tissue samples tested had detectable HHV-8 DNA seq u e n c e ~ . ’It~would ~ be unusual for a pathogen that is transmitted exclusively via sexual contact to be so prevalent in young children. Because a high concordance rate between maternal and childhood infection was present, perinatal transmission or transmission via breast-feeding are possible.’51Kasolo and colleagues collected blood and tissue samples of children who presented to a teaching hospital in Lusaka, Zambia with fever, atypical measles, or KS. Four of 53 febrile infants had HHV-8 DNA sequences detected in PBMCs, each with relatively high copy numbers per cell; these findings are consistent with primary

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infection in childhood that occurs with several herpesviruses.66The median age of the 10 childhood KS cases was higher in Kasolo's series than Ziegler's (9 versus 4 years); tissue from all 10 contained detectable HHV-8 DNA sequences.66 TREATMENT OF KAPOSI'S SARCOMA AND HUMAN HERPESVIRUS-8 INFECTION Chemotherapy

Because KS treatment is not curative, with the possible exception of ainterfer0n,7~most therapy is directed at palliation and cosmetic improvement.'" Many inconspicuous cutaneous lesions can be observed "off treatment," as progression is very slow. Limited disease is usually treated with local therapies that include radiation, intralesional chemotherapy, and surgical excision.1o4 Intralesional injection of vinblastine produces a response rate of 60% to %%, which persists for several Local pain and alterations in skin pigmentation may result. Use of the sclerosing agent, sodium tetradecyl sulfate, for the intralesional treatment of oral disease has been reported with good response Intralesional injection of a-interferon, or TNF-a produces high rates of complete response, although this effect occurs slowly.'34Side effects included local inflammation, pain, and systemic symptoms.104 Systemic therapy is indicated for extensive mucocutaneous disease or any visceral disease, lymphedema, or painful local lesions.'04 Interferon-a 2a or 2b have been evaluated in several trials and consistently produce a response rate of 30% to 45%.'" Highest response rates occur in patients without advanced HIV disease.'"* Adverse effects are common and include constitutional symptoms, mental status changes, nausea and vomiting, hepatotoxicity, hypotension, and neutropenia.'04 Cancer chemotherapy agents were used for classic and endemic KS prior to the AIDS epidemic.77The most active agents are bleomycin, doxorubicin, daunorubicin, liposomal doxorubicin, etoposide, paclitaxel, retinoic acid, teniposide, vinblastine, and vincristine, in combination or alone. Response rates to single-agent therapy vary from 17% to 94%, depending on the agent, stage of KS or HIV-related illness, and study design.'04 Response rates to combination therapies are higher (range, 43%-88%),8O although survival is not improved.104 Response rates may vary by study design and patient selection rather than efficacy of the treatment.lo4Toxicity is a major problem, although use of liposmal drug and hematopoietic growth factors can lessen its occurrence.8o Radiation Therapy

Radiation therapy (RT) in single or fractionated treatments is highly effective, and a particularly good choice for facial disease,'39 for painful or bulky local lesions or lymphedema.lo4Indications for RT in KS include pain, edema, bleeding or ecchymosis, cosmetic considerations and interference with ambulaSaran reported that 6 weeks after palliation, vision, nutrition, or re~pirati0n.I~~ tive RT, 32% of evaluable patients had a complete response, 55% had partial response, and 12% failed to respond.122Other studies have reported complete Higher doses tend to produce higher rates of response rates up to 85%.113 complete response.'39Early lesions respond more completely than mature ones, although residual pigmentation may persist.139

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Overall, conventional chemotherapy and RT offer palliation only, often in association with significant adverse effects. Given the recent understanding of the molecular factors that produce KS lesions and its characteristics, new treatments are being developed that target these key autocrine and paracrine factors. Novel Approaches to Kaposi's Sarcoma Therapy

Because KS is recognized to be a disease driven by paracrine and autocrine factors, cytokines and angiogenesis mechanisms may prove effective targets for the molecular-based approach to treatment.65Inhibitors of IL-6, such as retinoic acid, have been tried in limited studies. Although partial responses to transretinoic acid have been reported, caution must be exercised in the use of agents with such complex Von Roenn and colleagues found that retinoic acid paradoxically increased the size and number of KS lesions.145IFN-a may function as an inhibitor of angiogenesis in part via downregulation of b-FGF gene expressi0n.6~Human chorionic gonadotropin (HCG), used intralesionally45 or systemically,5* has been reported to induce regression in the size of KS lesions and complete remissions in a dose-dependent manner. Preparations of HCG contain various concentrations of several constituents, including P-HCG peptides that have strong inhibitory activity in vitro and in mouse models of KS.45P-HCG subunits resemble platelet-derived growth factor, which has been previously implicated in KS-induced edema.75Thalidomide, an inhibitor of TNF-a, has been reported to produce regression of KS lesions.129The observation that intravenous immunoglobulin treatment has been associated with regression KS lesions may also be based upon effects on the mediators of inflammation and angiogene~is.'~ Extracorporeal perfusion hyperthermia treatment has been reported to induce responses in 65% of patients, including sustained and complete responses in a few individuals, but appeared to be associated with fatal cardiac or central nervous system events, or intravascular coagulopathy in l2%.* Antiviral Therapies

If a herpesvirus is the causal agent of KS, and HIV synergistically promotes the development of the disease, antiviral therapeutic approaches make tremendous sense. Previous studies have shown that KS patients benefit from concurrent treatment for underlying HIV infection.80Findings of nucleoside agent trials demonstrate subtle beneficial effects on the course of KS.65More recently, protease inhibitor combination antiretroviral therapy has appeared to have induced the remission of KS lesions in a patient.Io5Protease inhibitor therapy has also been reported to result in the disappearance of detectable HHV-8 DNA from mononuclear cells in a patient who received the treatment for HIV infe~ti0n.I'~ Additional studies of the impact of antiretroviral therapy on the occurrence and course of KS are currently underway. Certain antiherpes drugs may influence the likelihood of KS occurring among HIV-infected persons. Mocroft and colleagues studied the records of 3688 HIV-infected patients who had been followed for a mean of 4.2 years. Foscarnet or ganciclovir use was associated with significant reductions in the subsequent occurrence of KS, but acyclovir had no such effectp*however, Humphrey, Yarchoan, and associates reported that the detection of HHV-8 DNA in PBMCs was not influenced by the intravenous administration of foscarnet or ganciclovir in a small number of patients.59

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SUMMARY

KS is a major cause of morbidity and mortality among AIDS patients and a treatment problem in the sporadic cases that are not associated with HIV. All four forms of the disease are linked to a newly described herpesvirus, HHV-8 or KSHV, via strong epidemiologic associations and biologic plausibility as a causal agent. HHV-8 is also epidemiologically associated with body cavity-based lymphomas, which are almost unique to AIDS, and Castleman’s disease. Existing radiation and chemotherapeutic treatments of KS are only partially effective and cause significant adverse effects. New preventive approaches and therapies aimed at inhibiting HHV-8 may be effective. New treatments that interfere with the molecular mechanisms that drive KS may, in the future, provide the best opportunities to control the disease. ACKNOWLEDGMENT The author expresses gratitude to Ilma Rodriguez for assistance in preparation of this manuscript and Nancy Hessol for editing it.

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