Study of HHV-8 DNA sequences in archival biopsies from lesional skin of Kaposi's sarcoma,various mesenchymal tumors and related reactive conditions

Background: HHV-8 has been identified as the causative agent of Kaposi's sarcoma (KS) and some lymphoproliferative disorders. In addition, there are anecdotal reports on the presence of HHV-8 in other tumors, especially cutaneous epithelial and mesenchymal neoplasms. The aim of the study was to ascertain the value of identification of HHV-8 viral DNA sequences in routinely processed, formalin-fixed, paraffin-embedded tissues for the diagnosis of Kaposi's sarcoma and other mesenchymal tumors.
Methods: The presence of HHV-8 sequences in archival material was studied by nested PCR using specific primers for amplification of a 233-bp long fragment of HHV-8 (ORF 26).
Results: Thirty-three patients with KS (18 classic/sporadic, six post-transplant and nine AIDS-related) and various mesenchymal tumors and related conditions (n = 76) were studied. HHV-8 DNA sequences were detected in 29 of the 33 cases of KS and in one case of multiple eruptive dermatofibroma (MEDF).
Conclusions: Identification of HHV-8 DNA sequences in routinely processed tissue is a useful diagnostic marker for KS. Although other mesenchymal tumors are usually not associated with HHV-8, its presence is not fully specific for KS since HHV-8 sequences were also found in one case of MEDF. Therefore, PCR analysis for the detection of HHV-8 should only be used as an additional diagnostic marker for KS and in the context of other tools such as routine histology.     

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.     

Clinical features and contribution of virological findings to the management of Kaposi sarcoma in organ-allograft recipients

OBJECTIVES: To describe the clinical features of Kaposi sarcoma (KS) in organ-allograft recipients and to determine the contribution of human herpesvirus 8 (HHV-8) investigations to the management of KS. DESIGN, SETTING, AND PATIENTS: We examined 20 organ-allograft recipients with KS at Pitié-Salpêtrière Hospital, Paris, France, between November 1, 1991, and May 31, 1999. METHODS: We detected HHV-8 antibodies using an indirect immunofluorescence assay and the HHV-8 DNA genome using nonnested polymerase chain reaction with KS-associated herpesvirus 330(233) primers in peripheral blood mononuclear cells collected at transplantation and KS diagnosis. We detected the HHV-8 genome in involved and uninvolved tissue specimens and in 10 patients' serum samples collected 1 month before the first manifestation of KS. We determined the HHV-8 double-strand DNA sequence and subtypes of open reading frame 26. INTERVENTION: Management of KS consisted of progressively tapering immunosuppressive therapy regardless of KS dissemination. Associated infections were treated when possible. Chemotherapy was prescribed only when a functional disability persisted, and polychemotherapy was prescribed for life-threatening disease. MAIN OUTCOME MEASURES: Percentage of recipients with KS remission and stabilization, organ-graft survival, and death rates. RESULTS: Remission of KS was obtained in 9 (45%) of the 20 patients independently of disease dissemination, with a mean follow-up of 35 months. The kidney graft survived in 12 (67%) of the 18 patients. Only 1 patient (5%) died of KS progression. All allograft recipients had anti-HHV-8 antibodies before transplantation. We detected HHV-8 DNA in all involved tissue samples but not in serum samples 1 month before KS onset. The most prevalent subtype was HHV-8 C (9 [53%] of 17 patients) and was not associated with extradermatological extension of KS compared with subtypes A and B'. CONCLUSIONS: Virological investigations of HHV-8 contribute poorly to KS management. Prospective studies are needed to determine the role of HHV-8 virological investigations and to identify associated cofactors so as to prevent KS in organ-allograft recipients.     

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.     

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.     

新疆Kaposi肉瘤组织内EBV,HHV—8双重感染的调查

应用ＰＣＲ方法，地２０例新疆Ｋａｐｏｓｉ肉瘤病理组织进行了ＥＢＶ和ＨＨＶ－８双重杂的调查，结果：２０例Ｋａｐｏｓｉ肉瘤病理组织中１４例检出ＨＨＶ－８ＤＮＡ（７０％），ＥＢＶ均为阴性。正常皮肤对照；１０例这两种疱疹类病毒均为阴性，作者认为新疆Ｋａｐｏｓｉ肉瘤的发生与ＥＢＶ的相关性很小，但明显与ＨＨＶ－８感染有关，但是否ＨＨＶ－８感染就是新疆Ｋａｐｏｓｉ肉瘤发生的决定因素，仍需进一步研究。     

HHV-8 DNA sequences in the peripheral blood and skin lesions of an HIV-negative patient with multiple eruptive dermatofibromas: implications for the detection of HHV-8 as a diagnostic marker for Kaposi's sarcoma

BACKGROUND: Multiple eruptive dermatofibroma (MEDF) is a rare disorder seen in immunocompromised patients, simulating Kaposi's sarcoma (KS). Whereas KS is strongly associated with human herpesvirus 8 (HHV-8), the virus has never been detected in MEDF until now. OBJECTIVE: To present a patient with MEDF who showed no signs of immunodeficiency but was seropositive for HHV-8 antibodies and demonstrated HHV-8 DNA both in the peripheral blood and lesional skin of MEDF. METHODS: Clinical, histological and serological investigations were performed as well as polymerase chain reaction (PCR) studies and in situ hybridization (ISH). RESULTS: A 35-year-old white man with suspected KS was referred for evaluation of multiple pigmented nodules and patches. Biopsies revealed features of dermatofibroma, superficial fibrosing dermatitis and scar. One of the nodular lesions harbored HHV-8 DNA sequences. A faint amplification product was detected in the superficial fibrosing dermatitis lesion, while no HHV-8 sequences were found in normal skin and scar. Whole-blood samples and serum were positive for HHV-8. None of the skin lesions shown to harbor HHV-8 DNA sequences by nested PCR displayed a signal for HHV-8 RNA by ISH. Repetitive peripheral blood examinations did not reveal any serum antibodies against or antigens of HIV. Serum antibodies against the HHV-8 capsid antigen orf 65.2 were detected. CONCLUSION: Results of PCR studies and ISH indicate that the presence of HHV-8 in the lesional tissue was probably blood-borne due to viremia and not due to viral replication in tumor cells. The presence of HHV-8 is not fully restricted to KS. The differential diagnosis of KS and its simulators should be based on an integrative analysis of all available clinicopathological and molecular data and should not rely exclusively or predominantly on the presence or absence of HHV-8.     

Angioedema in renal transplant recipients on sirolimus

BACKGROUND: Most drug-associated angioedemas are induced by angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, or nonsteroidal anti-inflammatory drugs. Recently, the responsibility of immunosuppressive agents given to transplant recipients in the development of angioedema has been discussed. OBJECTIVE: To describe, in detail, angioedema episodes in renal transplant recipients (RTRs) on sirolimus. METHODS: A cross-sectional study in a university hospital. Eighty consecutive RTRs on sirolimus were studied. RESULTS: Angioedema without urticaria occurred a mean of 5 times in 12/80 (15%) RTRs taking sirolimus. It was predominantly located on the face (83%), with mucous membrane involvement in 7 (58%) patients, and was life threatening in 1. Another putative cofactor for angioedema without urticaria was identified in 9 (75%) patients: drugs (n=8), food allergy or physical activity (n=3). Tacrolimus intake was significantly associated with sirolimus-associated angioedema. CONCLUSION: Our results suggested a causal relationship between sirolimus and angioedema in RTRs.     

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.     

新疆经典型Kaposi肉瘤29例血清HHV-8 DNA的套式PCR检测

目的了解新疆经典型Kaposi肉瘤(Kaposi’ssarcoma,KS)患者血清中人类8型疱疹病毒(humanherpesivirus8,HHV8)感染的情况,以探讨HHV8感染与经典型KS发病之间的关系。方法采用套式PCR技术检测29例新疆经典型KS及68例正常对照的血清中HHV8感染的情况。结果25例KS(86.2%)检测到HHV8的DNA片断;正常对照中14例(20.6%)检测到HHV8的DNA序列,差异有显著性(χ2=36.412,P<0.001)。结论HHV8在新疆经典型KS的发病中发挥着非常重要的作用,但可能不是发病的唯一原因。     

新疆Kaposi肉瘤组织内人类8型疱疹病毒DNA的检测

目的 了解Kaposi肉瘤组织内人类8型疱疹病毒(HHV-8)在Kaposi肉瘤发病中的作用。方法 应用荧光原位聚合酶链反应(PCR)方法对20例新疆Kaposi肉瘤组织进行HHV-8DNA检测,Kaposi肉瘤组织损害包括结节12份、斑块6份、斑片2份。同时和20份非Kaposi肉瘤组织,包括纤维瘤组织18份,血管瘤组织2份进行对照。结果 20例新疆Kaposi肉瘤组织中有17例检测到HHV-8DNA(阳性率为85%),而20例非Kaposi肉瘤组织HHV-8DNA均为阴性。两组阳性率经校正χ²检验,χ²=26.2,P<0.001.实验中HHV-8DNA片段主要集中于Kaposi肉瘤组织的梭形瘤细胞和血管内皮细胞。除此之外,在Kaposi肉瘤表皮角质形成细胞内也检测到HHV-8DNA片段,但DNA片段的荧光强度明显弱于梭形瘤细胞和血管内皮细胞中的荧光强度。结论 在新疆Kaposi肉瘤的发生中,HHV-8起着一定的作用,可能参与了Kaposi肉瘤的发病,但不是Kaposi肉瘤发生的唯一病因。     

Topical treatment of cutaneous Kaposi sarcoma with imiquimod 5% in renal-transplant recipients: a clinicopathological observation

Kaposi sarcoma (KS) is a vascular neoplasm pathogenetically linked to human herpesvirus 8. Transplant recipients, in particular renal-transplant recipients (RTRs) are at higher risk for post-transplant (P)-KS which affects 0.2-11% of RTRs. The course of P-KS is influenced by the post-transplantation immunosuppressive treatment. Reduction of immunosuppressive drugs can result in tumour regression, and is the treatment of choice for P-KS, but is associated with the risk for transplant rejection. Imiquimod is a topically applied immunomodulator without relevant systemic absorption, and may thus represent a promising treatment for cutaneous KS in RTRs. The aim of this study was to investigate the clinical and histological effects of imiquimod in two RTRs with cutaneous KS. Imiquimod resulted in complete clinical and histologically proven remission in one patient, but in the second patient, although there was clinical remission, histological persistence of KS was found. Imiquimod may represent an effective treatment for RTRs with cutaneous P-KS. However, clinical remission does not necessarily indicate complete tumour regression, as shown in one of our patients, who had a persisting tumour, as shown by biopsy examination. Thus, histological confirmation is crucial to confirm complete response.     

Infection of circulating CD34+ cells by HHV-8 in patients with Kaposi's sarcoma.

Human herpesvirus type 8 (HHV-8) has been identified as the most likely candidate to be involved in the development of Kaposi's Sarcoma (KS). HHV-8 has been associated with all forms of KS, primary effusion lymphoma, and multicentric Castleman's disease and detected in various non-neoplastic cells. Its presence in cells of the different hemopoietic lineages has not yet been investigated in a comprehensive and systematic manner. In this study we searched for the presence of HHV-8 in different subpopulations of peripheral blood mononuclear cells (PBMC) from patients with classic and AIDS-associated KS, as well as from HIV-1 sero-positive and sero-negative persons without KS. Thirty-four samples of PBMC were isolated from 30 patients. Subpopulations were isolated with immunomagnetic beads. Polymerase chain reaction for HHV-8 DNA was performed on PBMC and subpopulations with a primer pair selected from ORF26 of the viral genome. Polymerase chain reaction products were subsequently Southern blotted and hybridized. In patients with KS, HHV-8 DNA was detected in nine of 11 (81%) CD19+ cells, four of 11 (36%) CD2+ cells, three of 11 (27%) CD14+ cells, and nine of 11 (81%) of the remaining depleted cell populations (DP) that contain CD34 positive cells. In a subsequent set of experiments HHV-8 DNA was detected in 10 of 12 (83%) CD34 positive cell fractions. All cell subpopulations from the non-KS group were HHV-8 negative, with the exception of one positive B cell sample obtained from an HIV-infected patient. Our data demonstrate that in peripheral blood HHV-8 is detectable not only in CD19+ cells, as previously reported, but also in other cells, including T cells, monocytes, and cells devoid of specific lineage markers. We also show for the first time that CD34+ cells in peripheral blood of KS patients are a predominant HHV-8-harboring population, suggesting that they represent an additional important reservoir for this virus in vivo.     

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.     

Molecular analysis of Kaposi's sarcoma occurring during haemodialysis

Human Herpesvirus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). In this paper we attempted to confirm the connection between dialysis, HHV-8, and KS by examining the case of an elderly haemodialysis nonimmunosuppressed male patient with end-stage renal disease, who developed KS. By using PCR we have verified the presence of DNA from two different genomic regions (ORF 26 and ORF K1) of HHV-8. In addition, our RT-PCR results suggest active replication of HHV-8 in blood and KS lesions of the patient. Phylogenetic analysis revealed identical DNA sequence to ORF K1, and a close relation to its C1 variant. In conclusion, we document the case of KS and HHV-8 coexistence in a Greek elderly patient undergoing regular haemodialysis. Furthermore, our results indicate that factors other than immunosuppression could lead to KS development possibly due to activation of HHV-8.     

A case of classic Kaposi's sarcoma in a Japanese man: detection of human herpes virus 8 (HHV-8) infection by means of polymerase chain reaction and immunofluorescence assay

The recently discovered human herpes virus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). Because classic KS in Japan is rare and the detection of HHV-8 DNA by polymerase chain reaction (PCR) has been successful only in limited cases, the frequency and role of HHV-8 infection in KS in Japan remain unclear. Herein we report a case of classic KS in a Japanese man whose HHV-8 infection was confirmed by the detection of lesional viral DNA and serum antibodies against lytic antigen.     

HIV - associated and non - HIV associated types of Kaposi's sarcoma in an African population in Tanzania. Status of immune suppression and HHV-8 seroprevalence

In this study 77 patients with histologically confirmed Kaposi's sarcoma (KS) were seen at the Regional Dermatology Training Centre (RDTC) in Moshi, Tanzania. Sixty six patients (85.7%) were HIV-seropositive KS-patients (40 males, 26 females; male: female ratio 1.5:1), whereas another 11 (14.3%) KS-patients, all males, were found HIV-seronegative, thus corresponding to the endemic African KS-type. In both groups the CD4+ cell counts were generally low, the CD8+ population increased and the CD4+/CD8+ ratio inverted. Immune suppression was, however, more prominent in the HIV-seropositive group.HHV-8 seroprevalence was high in patients with HIV-associated KS (94.6%), nevertheless, 3 (5.4%) patients in this group remained HHV-8 seronegative. All nine patients with the HIV-seronegative African type of KS were found positive for HHV-8. Of the entire group seen, males were more likely to be HHV-8 seropositive than females (OR = 3.348 95% CI, 0.96-11.65; p < 0.05). The relative risk to develop KS in individuals seropositive to both HIV and HHV-8 was high (OR = 10.6, 95% CI; 2.981-37.688; p < 0.001).Overall, HIV-associated KS differed from the non-HIV-associated by its widespread clinical dissemination on the trunk, the frequent involvement of the oral mucosa and the craniofacial region, and its more rapidly progressive course. No histological differences between the two KS-groups were seen, although spindle cell infiltrates were more often found in the HIV-associated KS-group.     

HHV-8/KSHV during the development of Kaposi's sarcoma: evaluation by polymerase chain reaction and immunohistochemistry

The human gamma-herpes virus-8 (HHV-8) was first described in AIDS-related Kaposi's sarcoma (KS) tumour samples. In this study, we report comparative studies on paraffin-embedded biopsies of AIDS-related KS (AKS) and endemic KS (EKS) with regard to HHV-8 content as evaluated using polymerase chain reaction (PCR) and immunohistochemistry. DNA was extracted either using Chelex-100 or using Qia-gene kit and was evaluated with the help of a semiquantitative PCR assay. The PCR detection of HHV-8 was more sensitive to the Chelex method than to Qia-gene. The threshold for PCR test sensitivity with the help of serial dilution of DNA was at the level of five plasmid ORF-26 regions, and DNA from 25 body cavity-based lymphoma-1 cells. The results expressed as virus load/actin unit showed progressively higher HHV-8 levels in late (nodular) cases, compared to those in early (patch/plaque) stages. Evaluation of HHV-8 DNA levels in tumour tissues, thus, indicates a correlation between virus load and KS stage. Double immunostaining of spindle cells (SC) in KS biopsies for CD34 and HHV-8/latency-associated nuclear antigen (LANA) showed an increase in double-positive SC in the lesions of nodular AKS and EKS cases, compared to that in plaque and patch stages. However, 10-15% of CD34+/LANA- SC cells were observed during the development from patch to nodular cases of AKS and EKS. Our results indicate that PCR analysis is a simple and sensitive diagnostic method for HHV-8 evaluation in KS tissues, processed for conventional histopathology.     

Kaposi sarcoma associated with systemic corticosteroid therapy

Kaposi sarcoma (KS) was first described in 1872 by Moritz Kaposi. Its epidemiology is suggestive of an infectious disease and in 1994 Chang and coworkers identified DNA sequences corresponding to a previously unidentified herpes virus--human herpes virus 8 (HHV-8)--in AIDS-associated KS biopsies. It is now believed that the presence of HHV-8 is a necessary condition but not sufficient on its own to cause KS. Other factors such as immunosuppression should also be considered and it is known that immunosuppressive therapy increases the risk of KS. We describe a patient who developed KS after prolonged prednisone therapy for temporal arteritis.     

人类疱疹病毒8型基因型的研究进展

人类疱疹病毒8型广泛存在于各种临床表型的Kaposi肉瘤中,其基因型分布呈现种族与地域特异性.了解Kaposi肉瘤患者中HHV-8基因型特征及分布情况,探讨其与Kaposi肉瘤临床可能的相关性和演变及传播等具有重要意义.并对HHV-8病毒体及其基因组特征,K1和K15基因位点的生物学功能.HHV-8基因型演变呈现地域与种族特异性进行概述.