Human Herpesvirus 8 (HHV-8)

Authors: Harutaka Katano, D.D.S., Ph.D. , Tetsutaro Sata, M.D., Ph.D.

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VIROLOGY

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).

EPIDEMIOLOGY

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.

CLINICAL MANIFESTATIONS

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.

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.

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).

LABORATORY DAIGNOSIS

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).

PATHOGENESIS

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.

SUSCEPTIBILITY 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.

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.

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).

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.

ANTIVIRAL THERAPY

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.

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).

Primary Effusion Lymphoma

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

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.

ADJUNCTIVE THERAPY

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.

ENDPOINTS FOR MONITORING THERAPY

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.

VACCINES

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.

PREVENTION OR INFECTION CONTROL MEASURES

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.

COMMENTS

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.

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