人疱疹病毒8（HHV-8

译者：李卫霞医学博士

中国协和医科大学

审阅者：范洪伟副教授

北京协和医院感染科

Human herpesvirus 8 (HHV-8, Kaposi's sarcoma-associated herpesvirus, KSHV) was identified from acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma in 1994 (8). Both Epstein-Barr virus (EBV) and HHV-8 belong to the gamma-herpesvirus subfamily, and the latter is classified as a human g²-herpesvirus (25). HHV-8 has been detected in AIDS-associated and non-AIDS-associated Kaposi's sarcoma, primary effusion lymphoma, some cases of solid lymphoma and AIDS-associated multicentric Castleman's disease. Unlike other viruses, HHV-8 encodes several human homologues including cytokines (interleukin-6, macrophage inflammatory proteins, interferon-regulatory factors) and regulatory genes (cyclin D, G-protein coupled receptor, etc). These proteins may play important roles in the pathogenesis of HHV-8 (25).

　　1994年从获得性免疫缺陷综合症（AIDS）相关卡波西肉瘤中分离出人疱疹病毒8（HHV-8，卡波西肉瘤相关疱疹病毒，KSHV）（8）。Epstein-Barr病毒（EB病毒）和HHV-8都属于γ-疱疹病毒亚科，而后者被归为人g2-疱疹病毒（25）。AIDS相关和非AIDS相关的卡波西肉瘤、原发性浆膜腔性淋巴瘤、某些实体淋巴瘤和AIDS相关的多中心Castleman病中都能检测到HHV-8。与其他病毒不同，HHV-8能编码几种人类同源产物，包括细胞因子（白介素-6、巨噬细胞炎性蛋白、干扰素调节因子）和调控基因（细胞周期蛋白D、G蛋白耦联受体等）。这些蛋白在HHV-8的发病机制中起着重要作用（25）。

The seroprevalence of HHV-8 varies among ethic groups and geographic areas (25). Generally, HHV-8 infection is very common in African countries (30-50%), and common in certain Mediterranean countries (10-30%), but uncommon in Asian (2-4%) and northern and southern American countries (5-20%). Most individuals with HHV-8 infection are asymptomatic. HHV-8, however, is strongly associated with malignancies such as Kaposi's sarcoma and malignant lymphoma in immunocompromised persons such as those with AIDS and organ transplant recipients. The mode of transmission of HHV-8 remains unclear. Human immunodeficiency virus (HIV)-infected homosexual men without Kaposi's sarcoma demonstrate a high seroprevalence, whereas patients with HIV infection transmitted by transfusion or blood products demonstrate low seropositivity, suggesting that the predominant mode of transmission is sexual activity in those patients. Since the saliva of HHV-8 infected individuals contains high titer of HHV-8, saliva-mediated vertical or horizontal transmission is also likely to occur among younger people.

　　在不同民族和地区，HHV-8的血清阳性率不同（25）。大体上讲HHV-8感染在非洲国家很常见（30－50％），在某些地中海国家比较常见（10－30％），而在亚洲（2－4％）、北美和南美国家（5－20％）不常见。大多数HHV-8感染者没有症状。然而HHV-8与恶性疾病密切相关，如AIDS和器官移植等免疫抑制患者的卡波西肉瘤和恶性淋巴瘤。HHV-8的传播方式还不清楚。在无卡波西肉瘤的人免疫缺陷病毒（HIV）感染的男性同性恋者中，其血清阳性率高，而通过输血或血液制品而感染HIV的患者中，其血清阳性率低，说明性行为是这些患者的主要传播方式。由于HHV-8感染者的唾液中含有高滴度的HHV-8，因此在年轻人中，也可能会由唾液引发垂直或水平传播。

Kaposi's Sarcoma: Clinically, Kaposi's sarcoma is the most important disorder among HHV-8-associated diseases, because HHV-8-associated primary effusion lymphoma and multicentric Castleman's disease are rare. Kaposi's sarcoma was first described in 1872 as a rare hemangiosarcoma-like tumor seen in elderly men of Mediterranean descent (classic type) (1, 17). Recently, three additional clinical types have been recognized: AIDS-associated or post-transplantation Kaposi's sarcoma (due to acquired immunodeficiency) and African (endemic) Kaposi's sarcoma. AIDS-associated Kaposi's sarcoma occurs particularly in homosexual males. Skin lesions of Kaposi's sarcoma are clinically classified into the patchy, plaque and nodular stage. These skin lesions appear mainly in the extremities, but in more advanced cases appear as multiple ovoid-shaped skin lesions in the trunk symmetrically. Organ involvements are sometimes observed in the gastrointestinal tract and/or lungs, resulting in death. However, the progression of Kaposi's sarcoma depends on the host's immune status, and spontaneous regression of Kaposi's sarcoma is sometimes reported. Histologically, Kaposi's sarcoma is characterized by spindle cell proliferation accompanied by vascular slits. These spindle cells of Kaposi's sarcoma are infected with HHV-8 predominantly in the latent phase.

卡波西肉瘤：卡波西肉瘤是临床上最主要的HHV-8相关疾病，因为HHV-8相关的原发性渗出性淋巴瘤和多中心Castleman病罕见。1872年首次报道卡波西肉瘤，是罕见的地中海裔老年男性的血管肉瘤样肿瘤（经典型）（1，17）。最近又发现三种其它临床类型：AIDS相关或移植后卡波西肉瘤（由于获得性免疫缺陷）和非洲卡波西肉瘤（地方性）。AIDS相关卡波西肉瘤主要发生在男性同性恋人群中。卡波西肉瘤的皮肤病变主要在四肢，但进展期病例会在躯干出现对称性的多发卵圆形的皮损。此外，卡波西肉瘤可累及内脏造成死亡，例如消化道和/或肺脏。卡波西肉瘤的进展取决于宿主的免疫状态，有报道卡波西肉瘤可自然消退。卡波西肉瘤的组织学特征是梭形细胞增殖并有血管裂隙。卡波西肉瘤的梭形细胞潜伏感染HHV-8。

Primary Effusion Lymphoma: Primary effusion lymphoma is a rare disease occurring mainly in AIDS patients. Primary effusion lymphoma is diagnosed as a lymphomatous effusion in body-cavities such as pleural, abdominal, or pericardial effusion without a solid tumor mass (26). Although lymphoma cells have an undeterminant immunophenotype, B cell linage is suggested by rearrangement of the immunoglobulin gene. Primary effusion lymphoma has a poor prognosis. Generally, primary effusion lymphoma cells are latently infected with both EBV and HHV-8, and lymphoma cells contain a high copy number of HHV-8. However, recently some cases of EBV-negative and HHV-8-negative primary effusion lymphoma have been reported.

原发性浆膜腔性淋巴瘤：原发性浆膜腔性淋巴瘤罕见，主要见于AIDS患者。原发性浆膜腔性淋巴瘤不形成肿块，而是在体腔如胸腔、腹腔或心包的形成积液内有淋巴瘤细胞。尽管淋巴瘤细胞不具有明确的免疫表型，但通过免疫球蛋白基因重排提示肿瘤来自B细胞系。原发性浆膜腔性淋巴瘤预后较差。通常原发性浆膜腔性淋巴瘤细胞潜伏感染EBV和HHV-8，且淋巴瘤细胞中包含高拷贝数的HHV-8。然而最近有EBV阴性和HHV-8阴性的原发性浆膜腔性淋巴瘤的病例报告。

Multicentric Castleman's Disease: Multicentric Castleman's disease is a rare disease characterized by plasmacytic lymphoadenopathy with polyclonal hyperimmunoglobulinemia and high levels of interleukin-6 in the serum. Multicentric Castleman's disease is not malignancy, however the prognosis, especially of AIDS-associated multicentric Castleman's disease, is poor. Follicular hyperplasia with proliferation of plasma cells and hyaline vascular alterations in the lymph node are the histopathological hallmarks of multicentric Castleman's disease. HHV-8 is frequently detected in tissues obtained from patients with multicentric Castleman's disease associated with HIV infection (36, 38).

多中心Castleman病：多中心Castleman病是一种罕见疾病，其特点是浆细胞性淋巴结肿大，伴有多克隆高免疫球蛋白血症和高水平血清白介素-6。多中心Castleman病不是恶性疾病，但其预后较差，尤其AIDS相关的多中心Castleman病。淋巴结内滤泡增生伴有浆细胞增生和血管透明样变是多中心Castleman病的组织病理学特点。与HIV感染相关的多中心Castleman病患者的组织中常常能检测到HHV-8 (36, 38)。

The methodology of HHV-8 isolation from clinical samples has not been established. Polymerase chain reaction (PCR), in situ hybridization and immunohistochemistry are used for detection of HHV-8. Serum antibodies against latency-associated nuclear antigen, ORF59, ORF65, and K8.1 proteins are detected in the HHV-8-infected individuals using enzyme linked immunosorbent assay (ELISA) or immunofluorescence assay (18).

　　目前无法从临床标本中分离HHV-8。可以采用聚合酶链式反应（PCR）、原位杂交和免疫组化检测HHV-8。可以采用酶联免疫吸附试验（ELISA）或免疫荧光法来检测HHV-8感染者体内的潜伏相关核抗原、ORF59、ORF65和K8.1蛋白的血清抗体（18）。

A causal association of HHV-8 infection with Kaposi's sarcoma has been firmly established (25). DNA fragments of HHV-8 have been detected in more than 95% of Kaposi's sarcoma cases by PCR and anti-HHV-8 antibodies are detected in sera from patients with Kaposi's sarcoma, regardless of HIV infection. Immunohistochemical studies of Kaposi's sarcoma tissues show that HHV-8-encoded latency-associated nuclear antigen is expressed in nearly all Kaposi's sarcoma cells, whereas detection of lytic-antigen is very rare, suggesting that the latent infection of HHV-8 is predominant in these cells. It has been demonstrated that the function of p53 and retinoblastoma protein were inhibited by latency-associated nuclear antigen and viral cyclin D, another latent protein encoded by HHV-8, in vitro, respectively. Transgenic mice of viral G-protein coupled receptor carry Kaposi's sarcoma like region in the skin. These data suggest the oncogenesity of HHV-8 in vitro. Many cells expressing the lytic proteins are found in the multicentric Castleman's disease, suggesting that multicentric Castleman's disease has the different association with HHV-8 from HHV-8-associated malignancies such as Kaposi's sarcoma and primary effusion lymphoma.

　　HHV-8感染和与卡波西肉瘤的因果关系已经明确(25)。不论是否感染HIV，95％以上的卡波西肉瘤患者通过PCR法可以检测到HHV-8 DNA片段，血清中存在HHV-8抗体。卡波西肉瘤组织的免疫组化研究显示，几乎所有的卡波西肉瘤细胞中都表达HHV-8 编码的潜伏相关核抗原，而细胞裂解抗原很少，说明这些细胞中存在HHV-8的潜伏感染。体外研究已经证实，潜伏相关核抗原、病毒的细胞周期蛋白D（HHV-8编码的另一种潜伏蛋白）可以抑制p53和视网膜母细胞瘤蛋白的功能。G-蛋白耦联受体的转基因鼠会出现卡波西肉瘤样皮肤损害。这些资研究表明，在体外条件下，HHV-8具有致癌性。多中心Castleman病组织中有很多表达细胞裂解蛋白的细胞，说明多中心Castleman病与HHV-8的关系跟卡波西肉瘤、原发性渗出性淋巴瘤与HHV-8的关系不一样。

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

There are several reports describing HHV-8 infection experiments. Generally, HHV-8 does not easily infect cultured cells. In addition, HHV-8 infection results in latent infection; therefore, conventional assays detecting plaques caused by lytic infection in cells is not available for measuring the titer of virus like many other herpesviruses.

有文献报道HHV-8感染的试验模型。通常HHV-8不容易感染培养细胞。此外HHV-8感染是潜伏感染；因此，用产病毒感染引起细胞病变的常规方法不能检测大多数疱疹病毒的滴度。

An infection experiment reported by Dittmer et al. (12) is a model for clinical HHV-8 infection. HHV-8 virions were inoculated directly into severe combined immunodeficiency (SCID)-hu Thy/Liv mice. Real time quantitative PCR detected HHV-8 abundantly in CD19-positive lymphocytes. In this study, ganciclovir inhibited HHV-8 infection in the SCID-hu Thy/Liv mice.

　　Dittmer等（12）报道了HHV-8临床感染的模型。HHV-8病毒颗粒直接接种至重度联合免疫缺陷（SCID）-hu Thy/Liv小鼠。采用实时定量PCR法，在CD19＋淋巴细胞中可以检测到大量HHV-8。更昔洛韦可以抑制SCID-hu Thy/Liv小鼠的HHV-8感染。

BCBL-1, an HHV-8-infected cell line derived from a primary effusion lymphoma, produces HHV-8 particles in the culture supernatant after stimulation by phorbor-ester acetate (32) and up to 20% of primary effusion lymphoma cells were induced to lytic infection. In some studies, virus production by BCBL-1 cells was measured to estimate the efficiency of antiviral drugs. These studies indicated that HHV-8 replication is insensitive to acyclovir (50% inhibitory concentration [IC50] = 60-80 µM), but sensitive to ganciclovir (IC50 = 2.7-4.0 µM), foscarnet (phosphonoformic acid, IC50 = 80-100 µM), and cidofovir (IC50 = 0.5-1.0 µM) (20). Another study indicated that cidofovir and HPMPA [(S)-1-(3-hydroxy-2- phosphonylmethoxypropyl)adenine], a DNA polymerase inhibitor, could inhibit HHV-8 DNA synthesis, with 50% effective concentrations (EC50) of 6.3 and 0.6 :M, respectively (27). Adefovir, an acyclic nucleoside phosphonate with antiviral activity for both retroviruses and herpesviruses, and the N-7-substituted nucleoside analog S2242 (EC50, 0.11 µM) also blocked HHV-8 DNA replication (27). The mechanism of action of ganciclovir for inhibition of HHV-8 was investigated. HHV-8 ORF21 encodes a thymidine kinase (TK), and ORF36 encodes a phosphotransferase (PT) (7, 16). HHV-8-encoded TK phosphorylates ganciclovir, but its efficiency is low. However, the HHV-8-encoded PT phosphorylates ganciclovir more efficiently than the viral TK (7, 16).

　　BCBL-1是来自原发性浆膜腔性淋巴瘤的HHV-8感染的细胞系，用醋酸佛波酯刺激后，在培养上清液中产生HHV-8颗粒（32），20％的原发性浆膜腔性淋巴瘤细胞出现产病毒感染。有研究利用测定BCBL-1细胞产病毒的量来评估抗病毒药物的效果。这些研究结果提示，HHV-8的复制对阿昔洛韦不敏感（半抑制浓度[IC50] = 60-80 µM），对更昔洛韦（IC50 = 2.7-4.0 µM）、膦甲酸（磷酰基甲酸，IC50 = 80-100 µM）和西多福韦（IC50 = 0.5-1.0 µM）敏感（20）。另有研究提示，西多福韦和HPMPA[（R)-1-(3-羟基-2-磷酸甲氧基丙基)-腺嘌呤],一种DNA多聚酶抑制剂，可以抑制HHV-8 DNA合成，其半数有效浓度（EC50）分别为6.3 和0.6 μM（27）。阿德福韦对逆转录病毒和疱疹病毒属均有抗病毒活性，并且N-7替代核苷类似物S2242（EC50, 0.11 µM）也可以阻断HHV-8 DNA复制（27）。更昔洛韦抑制HHV-8的作用机制也进行了研究。HHV-8 ORF21编码胸苷激酶（TK），而ORF36编码磷酸转移酶（PT）（7，16）。HHV-8-编码的TK使更昔洛韦磷酸化，但其效能较低。而HHV-8-编码的PT磷酸化更昔洛韦的能力比病毒的TK强（7，16）。

These studies suggest that there is a possibility for antiviral therapy against HHV-8-associated diseases. However these reports investigated the ability of antiviral drugs to reduce lytic replication, while almost all primary effusion lymphoma cells are latently infected with HHV-8 without lytic replication. Therefore, it will be necessary to study the effects of the antiviral drugs on latent infection of HHV-8.

　　这些研究提示，抗病毒治疗可能对HHV-8相关疾病有效。但是这些报道研究的是抗病毒药物的抗产病毒复制的能力，而几乎所有的原发性浆膜腔性淋巴瘤细胞都是HHV-8潜伏感染，没有产病毒复制。因此必需研究抗病毒药物对HHV-8潜伏感染的作用。

General: To the best of our knowledge, there are no studies comparing antiviral drugs for the treatment of HHV-8 infections. At present, only experimental data in vitro and limited clinical data have been reported. All were retrospective studies and no antiviral drugs inhibited the growth of HHV-8-associated malignancies. Therefore, there is no definitive protocol or regimen for antiviral therapy of HHV-8-associated diseases.

概述：据我们所知，目前还没有比较抗病毒药物治疗HHV-8感染的研究。目前，仅有体外试验资料和有限的临床报道，都是回顾性研究，抗病毒药物不能抑制HHV-8相关恶性肿瘤的生长。还没明确的HHV-8相关疾病抗病毒治疗方案。

Kaposi's Sarcoma: There is no effective anti-HHV-8 therapy for Kaposi's sarcoma. Therefore, Kaposi's sarcoma is usually treated by irradiation, cytotoxic chemotherapy, or surgical resection (1). Some groups reported that antiviral drugs against herpes viruses have some prophylaxis activities on Kaposi's sarcoma in high risk patients (see VII).

卡波西肉瘤：尚无对卡波西肉瘤有效的抗HHV-8治疗。因此，卡波西肉瘤通常采用放疗、化疗或者手术切除（1）。有报道，在高危病人中，抗疱疹病毒药物对卡波西肉瘤具有一定的预防作用（见VII）。

Primary Effusion Lymphoma: Cytotoxic drugs are used for the treatment of primary effusion lymphoma and antiviral drugs are not effective.

原发性浆膜腔性淋巴瘤：原发性渗出性淋巴瘤用细胞毒药物治疗，抗病毒药物无效。

Multicentric Castleman's Disease: Many HHV-8-lytic infected cells are found in multicentric Castleman's disease lesions, suggesting that this disease could be more responsive to antiviral therapy (19, 31). However, there is no report describing the antiviral therapy against multicentric Castleman's disease. Recently, it was reported that the administration of an anti-CD20 antibody resulted in a remission of clinical symptoms and HHV-8 viremia, whereas other treatments including cidofovir, did not achieve durable clinical or virologic remission of the disease (9). Although the mechanism of anti-CD20 therapy remain unclarified, remission of HHV-8 viremia should be reflect a response in clinical symptoms.

多中心Castleman病：在多中心Castleman病的病灶中存在大量HHV-8产病毒感染的细胞，这提示抗病毒治疗会对该病有效（19，31）。但还没有多中心Castleman病抗病毒治疗的报道。最近有报道使用抗-CD20抗体使临床症状和HHV-8病毒血症缓解，而其它治疗包括西多福韦，不能获得持久的临床或者病毒学缓解（9）。尽管抗-CD20治疗的机制还不明确，但HHV-8病毒血症的缓解能反映临床症状的好转。

As mentioned previously, there is no specific antiviral therapy for HHV-8. Therefore, antiviral drugs cannot be the first choice for the treatment of HHV-8-associated diseases. In the case of classic Kaposi's sarcoma, which is not associated with HIV-infection, chemotherapy with cytotoxic drugs such as liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin, or radiation therapy and surgical resection should be the initial choices (1). While combination of doxorubicin, bleomycin, and vinblastine has shown some efficacy, the current therapy of choice is the single administration of liposomal-doxorubicin, with paclitaxel is as second-line therapy (15, 28, 34, 37). These drugs can induce bone marrow suppression. In the case of AIDS-associated Kaposi's sarcoma, radiation and chemotherapy are used and highly active anti-retroviral therapy (HAART) is known to be effective indirectly for Kaposi's sarcoma (6, 39, 40). In some cases HARRT alone resulted in regression of Kaposi's sarcoma (40). Another paper reported that the HHV-8 viral load in Kaposi's sarcoma skin lesions was suppressed by HARRT (3). Considering these reports, the growth of AIDS-associated Kaposi's sarcoma correlated with the degree of immune impairment of the host. The combination of interferon-alpha with zidovudine (10, 11, 21, 29), thalidomide (35), retinoic acid (5, 13), human chorionic gonadotropin (hCG) (14, 22) are also being tested, but these drugs are in the early experimental stage.

如上所述，针对HHV-8，没有特异的抗病毒治疗。因此抗病毒药物不是治疗HHV-8相关疾病的首选。经典的卡波西肉瘤与HIV感染不相关，首选的治疗是使用细胞毒药物进行化疗，例如脂质体蒽环类、紫杉醇、长春花碱和博来霉素，或者放疗或手术切除（1）。阿霉素、博来霉素和长春碱联合治疗有一定疗效，目前推荐多柔比星脂质体单药治疗，紫杉醇作为二线药物（15、28、34、37）。这些药物会引起骨髓抑制。AIDS相关的卡波西肉瘤可采用放疗和化疗，高效抗逆转录病毒治疗（HAART）对卡波西肉瘤有间接疗效（6、39、40）。单用HAART可使部分患者的卡波西肉瘤消退（40）。有文献报道HAART可以抑制卡波西肉瘤皮损中的HHV-8病毒载量（3）。根据这些报道，AIDS相关的卡波西肉瘤的发展与宿主免疫受损的程度有关。α-干扰素联合齐多夫定（10、11、21、29）、沙利度胺（35）、维甲酸（5、13）、人绒毛膜促性腺激素（hCG）（14、22）也都正在进行试验，但这些药物还在早期试验阶段。

Disappearance of tumors (Kaposi's sarcoma or primary effusion lymphoma) is an endpoint for the therapy. The viral load in the blood provides some information, but cannot be an indicator for the effects of the therapy.

　　肿瘤消失（卡波西肉瘤或原发性浆膜腔性淋巴瘤）是治疗的终点。血液中的病毒载量能提供一些信息，但不能作为疗效的指标。

Vaccine is the most effective method to prevent viral diseases, but there is no report describing a vaccine against HHV-8 at present. No vaccine against HHV-8 is commercially available, now.

　　疫苗是预防病毒性疾病的最有效方法，但目前还没有HHV-8疫苗的报道。目前在市场上没有HHV-8的疫苗。

It has been demonstrated that some antiviral drugs may have some effects on preventing the occurrence or progression of Kaposi's sarcoma in high-risk patients. A large study of more than 3,000 AIDS-patients showed that both foscarnet and ganciclovir might have some activity in preventing the occurrence of Kaposi's sarcoma, but that acyclovir had no benefit (24). Another study demonstrated that administration of foscarnet for cytomegalovirus retinitis resulted in a significant delay in the progression of Kaposi's sarcoma, as compared with ganciclovir (foscarnet; 211 days versus ganciclovir; 22 days) (33). Another group reported that oral or intravenous ganciclovir reduced the risk of developing Kaposi's sarcoma by 75 percent or 93 percent, respectively, as compared with placebo (23). These retrospective studies suggest that some anti-herpesvirus drugs such as ganciclovir or foscarnet may reduce the risk of developing Kaposi's sarcoma. However another study reported that intravenous ganciclovir or foscarnet therapy for the treatment of cytomegalovirus disease did not affect the HHV-8 DNA load in peripheral blood mononuclear cells of the patients (4), suggesting that these drugs do not directly affect growth of latently infected Kaposi's sarcoma cells.

　　已经证实，在高危人群某些抗病毒药物具有一定的预防卡波西肉瘤发生或进展的作用。一项超过3000名AIDS病人参加的大规模试验显示，膦甲酸和更昔洛韦可能具有预防卡波西肉瘤发生和发展的作用，但阿昔洛韦无效（24）。另一项研究发现，同更昔洛韦相比，使用膦甲酸治疗巨细胞病毒视网膜炎，会显著延缓卡波西肉瘤进展（膦甲酸211天，更昔洛韦22天）（33）。另一组研究报道，和安慰剂相比，口服或静脉注射更昔洛韦，发生卡波西肉瘤的风险分别下降75％和93％。这些回顾性研究显示，部分抗疱疹病毒药物，例如更昔洛韦或膦甲酸，可能会降低发生卡波西肉瘤的风险。但有也有研究报道，使用静脉注射更昔洛韦或膦甲酸，治疗巨细胞病毒病，不影响患者外周血单核细胞中的HHV-8 DNA载量（4），说明这些药物不直接影响潜伏感染的卡波西肉瘤细胞的生长。

There are some prospects for antiviral therapy against HHV-8. HHV-8-encoded latency-associated nuclear antigen is expressed in the cells of HHV-8-associated diseases (19, 31), indicating that HHV-8-associated diseases are associated with latent viral infection like EBV. Recently, it was demonstrated that latency-associated nuclear antigen bound to cellular chromosome and functioned to transmit HHV-8 DNA to daughter cells during mitosis (2). In order to inhibit this transmission, it is necessary to reduce not only lytic replication of the virus, but also the number of latently-infected cells. In that sense, development of antiviral drugs against HHV-8 will still be limited by the problem of latent infection. Recently some cytotoxic T lymphocytes targeting HHV-8 encoded proteins were identified in vivo (30). It is known that regression of Kaposi's sarcoma lesions is associated with infiltration of lesions by CD8-positive cells, and that the level of HHV-8 DNA decreases in regressing Kaposi's sarcoma lesions. Therefore, cytotoxic T lymphocyte activity specific for HHV-8 proteins is a major pathway for the regression of Kaposi's sarcoma. In future, infusion of HHV-8 specific cytotoxic T lymphocytes, generated in vitro by incubating lymphocytes with irradiated HHV-8 infected cells in the presence of interleukin 2, might also be used. Similar cellular therapies have been effective for treatment of EBV related malignancy.

　　HHV-8的抗病毒治疗有一定的前景。HHV-8相关疾病的细胞中有HHV-8编码的潜伏相关核抗原表达（19、31），这说明HHV-8相关疾病与病毒潜伏感染有关，如同EBV一样。目前已经证实，潜伏相关核抗原与细胞染色体结合，其功能是在有丝分裂时将HHV-8 DNA传递至子细胞中（2）。为了抑制这种传递作用，不仅需要降低产病毒复制，而且也要降低潜伏感染的细胞数量。从该意义上讲，潜伏感染依然限制了针对HHV-8的抗病毒药物的研发。目前在体内已经发现针对HHV-8编码蛋白的细胞毒T淋巴细胞（30）。现在已经知道，卡波西肉瘤的消退与病变内CD8阳性细胞浸润有关，在消退的卡波西肉瘤病变里面，HHV-8 DNA水平降低。因此，HHV-8蛋白特异的细胞毒性T淋巴细胞是卡波西肉瘤消退的主要原因。将来，在体外将淋巴细胞与照射过的感染细胞和白介素2共同抚育，获得HHV-8特异性细胞毒T淋巴细胞，可以输注这种细胞来进行治疗。类似细胞治疗已经有效地治疗EBV相关恶性疾病。

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