Kaposi's sarcoma and other manifestations of human herpesvirus 8

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.     

Kaposi肉瘤组织内人类疱疹病毒8型的K15基因型研究

目的 了解Kaposi肉瘤组织中人类疱疹病毒8型(HHV-8)K15等位基因型分布情况,并初步探讨Kaposi肉瘤不同临床分型及临床表现与不同HHV-8 K15等位基因型的相关性.方法 采用酚-氯仿-异戊醇法对收集的27例Kaposi肉瘤石蜡包埋组织标本进行病毒DNA抽提,并使用巢式PCR扩增K15基因片段,然后测序并确定其等位基因型.结果 27例Kaposi肉瘤中有22例HHV-8感染为阳性,阳性率为81.48%,其中4例艾滋病-Kaposi肉瘤患者HHV-8感染均为阳性,感染率100%;在分析的22例HHV-8病毒株中,20例为P型,2例为M型;4例艾滋病-Kaposi肉瘤患者感染的均为P型HHV-8,2例M型感染者均为经典型Kaposi肉瘤患者.结论 Kaposi肉瘤组织内HHV-8的K15等位基因型主要是P型,也存在部分M型HHV-8感染者.4例艾滋病-Kaposi肉瘤患者感染的HHV-8均为P型.     

Kaposi肉瘤组织内人疱疹病毒8型的K14.1基因型研究

目的:确定人疱疹病毒8 型K14.1基因等位基因型在Kaposi肉瘤中的分布,及与Kaposi肉瘤临床分型的关系.方法:使用酚-氯仿-异戊醇法对32例Kaposi肉瘤石蜡包埋组织进行病毒DNA提取,使用PCR法扩增K14.1基因片段,然后确定其等位基因型.结果:32 例中有27 例人疱疹病毒8型感染为阳性,阳性率为84.38%,其中5例艾滋病相关型KS患者HHV-8感染均为阳性,感染率100% ;在分析的27 例HHV-8病毒株中,24例为P等位基因型(包括5例艾滋病相关型KS患者皮损),3例为M等位基因型(均来自经典型KS).结论:本研究中,Kaposi肉瘤感染的人疱疹病毒8型的K14.1等位基因型以P等位基因型为主.     

Human herpesvirus 8 (HHV-8) in familial Kaposi's sarcoma

Human herpesvirus 8 (HHV-8) has been detected in various epidemiological forms of Kaposi's sarcoma (KS). Since familial KS cases are exceedingly rare and the occurrence of familial KS in siblings has thought to depend rather on genetic factors than on a viral factor, familial KS has not been investigated for the presence of HHV-8. To investigate whether HHV-8 is present also in this rare form of KS, we examined tumor biopsies of 2 siblings with familial KS for the presence of HHV-8 specific DNA sequences by a nested PCR protocol. HHV-8 DNA sequences could be detected in KS specimens of both patients. Sequence analysis revealed an identical DNA sequence of HHV-8 in KS tissue of both siblings, but the sequence in our cases differs in one base pair at position 67 from the previously published HHV-8 KS330Bam fragment. The findings indicate that besides the yet poorly defined genetical factors involved in the pathogenesis of KS, HHV-8 may act as a cofactor also in familial KS. In addition, our data demonstrate that HHV-8 is found in all epidemiological forms of KS, including the rarely occurring familial KS. Familial KS may act as a further model to study the interaction of an oncogenic virus with genetic host factors in the context of a neoplastic disorder.     

Seroprevalence of human herpesvirus 8 and its association with Kaposi sarcoma in Brazil

BACKGROUND: Epidemiologic studies have indicated that human herpesvirus 8 is implicated in the development of Kaposi sarcoma in different geographic areas worldwide. GOAL: To provide information on the prevalence of human herpesvirus 8 in Brazil and its association with Kaposi sarcoma. STUDY DESIGN: An immunofluorescence assay was performed to test 1,044 serum samples from 747 blood donors, 73 patients presenting to casualty departments, and 224 patients attending sexually transmitted disease/AIDS clinics. The sexually transmitted disease group was composed of 88 patients with HIV (40 Kaposi sarcoma positive, 48 Kaposi sarcoma negative) and 136 patients without HIV. RESULTS: Antibodies to human herpesvirus 8-latent nuclear antigens were found in 34 blood donors (4.6%), and in seven casualty patients (9.6%). The highest frequency of human herpesvirus 8 antibodies was found in the sexually transmitted disease group: 32 HIV-positive patients with Kaposi sarcoma (80%) and seven patients without Kaposi sarcoma (14.6%). CONCLUSION: The presence of human herpesvirus 8 in patients with HIV was strongly associated with Kaposi sarcoma (odds ratio, 23.4; 95% CI, 7.7-71.4), male gender, homosexual or bisexual orientation, and hepatitis B virus infection, but not with the other sexually transmitted diseases that were investigated.     

Simultaneous onset of primary cutaneous B-cell lymphoma and human herpesvirus 8-associated Kaposi's sarcoma

We report the simultaneous occurrence of Kaposi's sarcoma (KS) and primary cutaneous B-cell lymphoma (CBCL) of the leg in a 79-year-old woman, seronegative for HIV-1, HTLV-1 and HTLV-2. The CBCL underwent complete clinical remission after local radiotherapy, whilst the KS became disseminated within a year following diagnosis. However, 2 years after the diagnosis of KS, the patient died with neurological symptoms. These were presumed to be due to involvement of the central nervous system by lymphoma, although in the absence of an autopsy, this could not be proven. Skin biopsies from the original KS and CBCL lesions, as well as short-term culture of spindle cells from the KS lesion and peripheral blood mononuclear cells (PBMC), were studied by semiquantitative polymerase chain reaction (PCR) using primers specific for DNA sequences of a novel γ-herpesvirus-8 (HHV-8). PCR studies were strongly positive for the virus on KS cells and PBMC; conversely, a low viral load was found on CBCL cells. A high titre of serum IgG antibodies reacting with the nuclei of the HHV-8 positive cell line BCP-1 was found. These data suggest that reactivation of latent infection with HHV-8 had occurred in this patient, and that HHV-8 is directly involved in KS, but not in CBCL of the leg, an aggressive variant of CBCL.     

Infection with Kaposi's sarcoma-associated herpesvirus among families of patients with classic Kaposi's sarcoma

BACKGROUND: Classic Kaposi's sarcoma (CKS) primarily affects elderly Mediterranean or Eastern European men. Incidence rates of CKS in Israel are among the world's highest. In practically all cases, antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) can be detected. A relatively high seroprevalence rate of KSHV in Israel generally correlates with the incidence of CKS. A sexual mode of virus transmission is recognized among homosexual men, whereas the precise transmission routes in the heterosexual population and those with CKS are still unclear. OBJECTIVE: To better assess the transmission routes of KSHV in Israeli patients with CKS and their first-degree relatives as compared with a control group. DESIGN: Serum was collected from all study participants and tested for KSHV antibodies by means of latent and lytic immunofluorescence assays. An open reading frame 65 (ORF65) Western blot assay was applied as a confirmatory tool. SETTING: Three dermatological departments in Israel. PATIENTS: Sixty-four Jewish patients with CKS, 143 of their first-degree relatives, and 186 hospital-based control subjects. RESULTS: Seropositivity to KSHV was detected in 62 (96.9%) of the patients with CKS, in 56 (39.2%) of their first-degree relatives, and in only 21 (11.3%) of the hospital controls (P<.001). The specific relationship with the index patient (spouse, offspring, or sibling) had no significant effect on the prevalence of serpositivity in the family members. CONCLUSION: Our serologic evidence of familial clustering of KSHV infection suggests a predominantly nonsexual horizontal transmission route of the virus.     

Serological and immunohistochemical detection of human herpesvirus 8 in Kaposi's sarcoma after immunosuppressive therapy for bullous pemphigoid

Kaposi's sarcoma (KS) developed in an 87-year-old human immunodeficiency virus-negative woman from Hokkaido island 4 months after oral administration of prednisolone for the treatment of bullous pemphigoid (BP), and rapidly disseminated to almost the entire body within 2 months. The open reading frame (ORF) 59 and ORF73 proteins encoded by human herpesvirus 8 (HHV-8) were detected immunohistochemically in the nuclei of the tumour cells of KS. The protein coded by ORF73, latent protein, was detected in most of the nuclei of the tumour cells, but only a few tumour nuclei were positive for the ORF59 protein, a lytic protein expressed during active infection. The antibodies against both lytic and latent proteins of HHV-8 were detected retrospectively in the serum 4 months before the appearance of KS and before prednisolone therapy had been started. Immunosuppression associated with the treatment for BP possibly activated latent HHV-8 infection and induced the development of KS.     

Kaposi's sarcoma-associated herpesvirus viremia is associated with the progression of classic and endemic Kaposi's sarcoma

In order to gain further insight on the role of Kaposi's sarcoma-associated herpesvirus (KSHV) in classic and endemic Kaposi's sarcoma (KS) pathogenesis, we aimed to determine (i) whether KSHV is detectable in peripheral blood mononuclear cells (PBMCs), (ii) which PBMCs subpopulation harbor the virus, (iii) which clinical, histologic, and immunologic parameters are associated with KSHV viremia in a population of classic and endemic KS. KSHV viremia and various immunologic parameters were screened on 81 patients. KSHV viremia was positive in 58% of the patients. KSHV was detected in B cells, T cells, and monocytes. CD34+ cells depleted in circulating endothelial cells (CECs) were never infected and 50% of the patients tested had CECs infected by KSHV. We observed a significant increase of IL-2 and IFN-gamma production by CD4 T cells and an increase of IFN-gamma production by CD8 T cells compared to control patients. KS progression (P = 0.001) and KS staging (P = 0.03) were significantly and independently associated with positive KSHV viremia. Our results show that there is no specific immunosuppression in classic or endemic KS. We showed that KSHV can be detected within CECs and that KSHV viremia could be an indicator of circulating mature or precursor spindle cells.     

Transcripts of the human herpesvirus 8 genome in skin lesions and peripheral blood mononuclear cells of a patient with classic Kaposi's sarcoma

We report a 75-year-old Japanese woman with classic Kaposi's sarcoma. PCR amplified human herpesvirus 8 (HHV-8) DNA sequences from her skin lesions and peripheral blood mononuclear cells (PBMC), but not her plasma, saliva or urine. An antibody test against HHV-8 lytic antigens was positive. Immunohistochemical staining detected latent antigen. There was no evidence of HHV-8 infection in her husband, sister or daughter. Genes coding for HHV-8-encoded viral interleukin-6, viral macrophage inflammatory protein I, viral G protein-coupled receptor, viral cyclin D and viral Bcl-2 were expressed to the same degree in both her skin lesion and PBMC. Latency-associated T0.7 mRNA and HHV-8-encoded viral tegument protein genes were expressed in her PBMC at levels lower than in the skin lesions. Based on the gene expression profile, we concluded that lytic HHV-8 infection was present in her skin lesions and PBMC.     

Human herpesvirus 8 DNA in the skin and blood of patients with Mediterranean Kaposi's sarcoma: clinical correlations

BACKGROUND: Kaposi's sarcoma is a multifocal lympho-angioproliferative disease that appears in elderly subjects of Mediterranean origin (classical form), young Africans and immunodepressed patients (as a result of organ transplantation or AIDS). In 1994, DNA sequences of a new human herpesvirus, called HHV-8, were detected in skin lesions and peripheral blood of patients with AIDS-related Kaposi's sarcoma by confirmational display analysis and polymerase chain reaction. OBJECTIVE: As HHV-8 in peripheral blood mononuclear cells is detected in about 50% of Mediterranean Kaposi's sarcoma patients and its presence fluctuates in time in the same patient, maybe its detection correlates with the clinical behaviour of the disease. METHODS: By using routine and nested polymerase chain reaction we evaluated the presence of HHV-8-specific DNA sequences in the skin lesions, perilesional healthy skin and peripheral blood mononuclear cells of a group of 40 HIV-negative patients with Mediterranean Kaposi's sarcoma. RESULTS: HHV-8 DNA sequences have been found in 40/40 (100%) lesional skin of Mediterranean Kaposi's sarcoma, in 35/40 (85%) perilesional apparently normal skin and in 24/40 (60%) peripheral blood monuclear cell samples. The results of polymerase chain reaction on peripheral blood monuclear cells were positive in 41% of the patients with slowly evolving disease as opposed to 74% of those with rapidly evolving disease, and in 47.6% of the patients with stage I-II disease as opposed to 73.6% of those with stage III-IV. CONCLUSION: The detection of HHV-8 in peripheral blood monuclear cells seems to correlate with the more aggressive stages and the rapid evolution behaviour of Mediterranean Kaposi's sarcoma.     

Asymmetrical transmission of human herpesvirus 8 among spouses of patients with Kaposi sarcoma

Background  Among heterosexuals, the sexual transmission of human herpesvirus 8 (HHV8) has not been established.
Objectives  To assess HHV8 seroprevalence in spouses of patients with classic and endemic Kaposi sarcoma (KS) and to suggest possible routes of transmission.
Methods  A case–control study was carried out in a teaching hospital among spouses of human immunodeficiency virus-negative patients with KS (cases – exposed subjects) and controls who did not have KS nor were related to patients with KS (nonexposed subjects). HHV8 seroprevalence in spouses of patients with KS was compared with HHV8 seroprevalence in controls matched for age, gender and place of birth. Other serology tests were compared between cases and controls. Among heterosexual couples, HHV8-seropositive and HHV8-seronegative spouses were compared for possible risk factors for virus transmission.
Results  HHV8 seroprevalence was significantly higher among spouses of patients with KS (13 of 22; 59%) than among matched controls (19 of 58; 33%; P  =   0·043). Among heterosexual couples, five of five (100%) male spouses were HHV8 positive vs. six of 15 (40%) female spouses ( P  =   0·04). There was no significant difference between HHV8-seropositive and HHV8-seronegative spouses for all other factors screened for among heterosexual couples.
Conclusions  Being a spouse of a patient with KS is a risk factor for HHV8 seropositivity. Our results suggest that female-to-male HHV8 transmission could be more efficient than male-to-female transmission among couples including a patient with KS. Transmission could involve distinctive behaviours, or currently unknown biological properties of HHV8.     

Kaposi肉瘤组织内人类疱疹病毒8型K1基因型的初步分析

A5和C7亚型,与非洲和欧洲来源毒株的同源性很高.     

人疱疹病毒8型ORF26单核苷酸多态性研究

目的 探讨人疱疹病毒8型(HHV-8)ORF26的单核苷酸多态性,分析其与Kaposi肉瘤不同临床分型及黏膜侵袭性的相关性.方法 Kaposi肉瘤患者32例,其中经典型26例,艾滋病相关型6例.使用酚-氯仿-异戊醇方法对Kaposi肉瘤石蜡包埋组织进行HHV-8 DNA抽提,采用巢式PCR方法扩增ORF26基因并双向测序,使用DNAStar软件和Clustal W软件分析ORF26基因的单核苷酸多态性.运用Fisher确切概率法对结果进行统计学分析.结果 ORF26基因研究发现,32例Kaposi肉瘤患者中HHV-8阳性30例,6例艾滋病相关型HHV-8均为阳性.30例患者的病毒株中,HHV-8 ORF26基因SNP主要集中在981T/C( 12例)、1086C/T(12例)、1139A/C(12例);HHV-8 ORF26基因单核苷酸多态性在不同临床分型或有无黏膜损害的Kaposi肉瘤之间的差异无统计学意义.结论 HHV-8 ORF26基因单核苷酸多态性可能与Kaposi肉瘤不同临床分型和黏膜侵袭性无关.     

人疱疹病毒8型ORF75基因亚型与Kaposi肉瘤的相关性研究

目的 探讨人类疱疹病毒8型(HHV-8)ORF75基因亚型,与Kaposi肉瘤不同临床分型及侵袭性的相关性.方法 对25例新疆Kaposi肉瘤石蜡包埋组织进行HHV-8 DNA抽提、扩增及双向测序,使用Clustal W软件和PHYLIP软件包对测序结果进行发生学分析,从而确定HHV-8 ORF75基因哑型.结果 25例Kaposi肉瘤中,21例HHV-8阳性,阳性率为84%,其中7例AIDS相关型Kaposi肉瘤患者HHV-8均阳性.21例HHV-8阳性患者中,18例为HHV-8 ORF75 A亚型,3例为C亚型;不同亚型间Kaposi肉瘤患者有无黏膜损害及临床分型的分布差异均无统计学意义(P＞0.05).结论 新疆Kaposi肉瘤患者感染HHV-8 ORF75亚型属于A亚型和C亚型,HHV-8 ORF75不同亚型可能与新疆Kaposi肉瘤黏膜损害及临床分型无关.     

Detection of human herpesvirus 8 in Korean Kaposi's sarcoma cases by polymerase chain reaction and in situ polymerase chain reaction.

Several infectious agents, including herpesvirus-like particles, had been suggested as possible candidates for the development of Kaposi's sarcoma (KS), and a new herpesvirus, human herpesvirus 8 (HHV-8), was recently identified in the vast majority of KS lesions, irrespective of their association with human immunodeficiency virus (HIV) infection. However, the etiologic role of HHV-8 in KS remains controversial. We undertook this study to screen for and localize the presence of HHV-8 in KS in Korea. A total of 46 paraffin-embedded specimens were studied, including KS, hemangioproliferative disorders, and 10 non-KS lesions from HIV-positive patients. We performed nested polymerase chain reaction (PCR) and in situ PCR with HHV-8 specific primers. HHV-8 DNA sequences were detected in 8 of 11 KS specimens. All specimens of hemangioproliferative disorders, non-KS lesions from HIV-positive patients, and other skin samples were negative for HHV-8. When sequencing PCR products, the sequences were almost identical with the prototypic sequence for HHV-8. In PCR-positive tissues, in situ PCR staining of HHV-8 localized to nuclei of endothelial cells and perivascular spindle-shaped tumor cells. The results of this study suggest that HHV-8 is not widespread and has a certain causative role in the development of KS. Further studies, including serological and animal studies, will be helpful to appreciate an epidermiological link and pathogenetic mechanism between HHV-8 and KS.