Brenda L. Tesini, Mary T. Caserta
Human herpesvirus 8 (HHV-8) is an oncogenic virus identified in tissue specimens from patients with Kaposi sarcoma (KS). Because of this association, it is also known as Kaposi sarcoma–associated herpesvirus . HHV-8 is the etiologic agent of two additional lymphoproliferative disorders: primary effusion–based lymphoma (PEL) and multicentric Castleman disease (MCD) .
HHV-8 is a γ2 -human herpesvirus similar to Epstein-Barr virus. The virus contains a large DNA genome encoding 85-95 unique proteins. Infection is followed by both lytic and latent viral states with different degrees of viral replication associated with distinct disease manifestations.
The prevalence of infection with HHV-8 varies both geographically and by population and roughly matches the epidemiology of KS. HHV-8 infection is endemic in Africa and parts of South America, with infection rates of up to 30–60% by adolescence. Seroprevalence >20% has also been found in regions bordering the Mediterranean. In contrast, infection rates <5% are noted in North America, central Europe, and Asia. However, within geographic regions, the prevalence of infection varies with risk behaviors, rates of 30–75% being found among men who have sex with men in North America and Europe. HHV-8 DNA can be detected in saliva, blood, semen, and tissues. Based upon large-scale epidemiologic studies and the high prevalence of viral shedding in oral secretions, saliva is believed to be the major mode of transmission. Other less-common routes of HHV-8 transmission include blood transfusion, bone marrow transplantation, and solid organ transplantation. Vertical transmission and transmission via breast milk may occur in regions where HHV-8 is highly endemic, but the risk appears low.
HHV-8 contains multiple genes that impact cell-cycle regulation and the host immune response. Viral proteins interfere with the function of the tumor suppressor molecules, induce the expression of proangiogenesis factors, and lead to upregulation of the rapamycin pathway target, which is instrumental in the control of cell growth and metabolism. HHV-8 also encodes a homolog of human interleukin-6, which can bind and activate cytokine receptors and serve as a host cell autocrine growth factor. Additionally, viral proteins are associated with the constitutive expression of the transcription factor nuclear factor-κB. All of these proteins may be potential targets for therapeutic intervention.
Although subclinical infection appears to be common, symptomatic primary HHV-8 infection has been described in immunocompetent children. Patients commonly have fever and a maculopapular rash or a mononucleosis-like syndrome, with full recovery the rule. In immunocompromised patients, primary infection has been associated with fever, rash, splenomegaly, pancytopenia, and lymphoid hyperplasia, and may be quite severe. Additionally, preliminary data suggest that transfusion-associated primary infection with HHV-8 is associated with an increased risk of mortality.
Even in regions with high rates of seroprevalence, the development of KS is uncommon. KS has several different clinical forms; each includes multifocal, angiogenic lesions arising from vascular endothelial cells infected with HHV-8. Classic KS is an indolent disorder seen in elderly men with limited involvement of the skin of the lower extremities. Endemic KS is more aggressive, occurring in children and young people, primarily in Africa, and can include visceral involvement as well as widespread cutaneous lesions (patches, plaques, or nodules). Posttransplantation KS and AIDS-related KS are the most severe forms, with disseminated lesions, often in the gastrointestinal tract and lungs, with or without cutaneous findings.
Primary effusion–based lymphoma is a rare disease caused by HHV-8 that is seen most commonly in HIV-infected individuals. It consists of lymphomatous invasion of the serosal surfaces of the pleura, pericardium, and peritoneum. Similarly, multicentric Castleman disease is an unusual lymphoproliferative disorder characterized by anemia, thrombocytopenia, generalized lymphadenopathy, and constitutional symptoms and frequently associated with HHV-8 infection and a high degree of viral replication.
Serologic assays, including immunofluorescence and enzyme-linked immunosorbent assays, are the primary methods of diagnosing infection with HHV-8. However, testing has limited sensitivity, specificity, and reproducibility and is primarily a research tool with no universally recognized standard assays. Additionally, the loss of antibodies over time, referred to as seroreversion, has been described, further complicating serodiagnosis. Immunohistochemistry and molecular methods are available for the detection of HHV-8 in tissue samples and are utilized in the diagnosis of KS, PEL, and MCD, alongside their disease-specific clinical manifestations.
Treatment for KS, PEL, and MCD is multifaceted and includes attempts to control malignant proliferations with traditional chemotherapeutic regimens and biologic agents as well as agents aimed at specific cellular pathways targeted by HHV-8 proteins. Combined antiretroviral therapy (ART) is a mainstay of both prevention and therapy for HHV-8 related disease in HIV-infected patients. In HIV-associated KS, treatment with ART alone is often used for the control of mild (i.e., cutaneous) disease, while ART plus chemotherapy is utilized for more severe disease. In transplantation-associated KS, the first line of treatment includes decreasing immunosuppression, often in association with a switch from calcineurin inhibitors to sirolimus (rapamycin) to block the mammalian target of rapamycin pathway. Severe disease frequently requires the use of traditional chemotherapy as well. The role of specific antiherpesvirus antiviral treatment is unclear. Oral valganciclovir decreases the detection of HHV-8 in saliva, and ganciclovir treatment has been associated with decreased rates of development of KS in HIV-infected individuals. However, results of using antivirals in the treatment of established disease have been generally disappointing. The prognosis for PEL tends to be poor despite the use of traditional chemotherapy, while rituximab (anti-CD20)–based therapy has been highly successful for MCD treatment. However, relapse and the development of lymphoma following treatment can still occur. Rituximab treatment may also worsen concurrent KS without additional agents.