Etiology

HHV-8 is a γ-2-human herpesvirus genetically most similar to Epstein-Barr virus. The virus contains a large DNA genome encoding for 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.

Epidemiology

The prevalence of infection with HHV-8 varies both geographically and by population and roughly matches the epidemiology of KS. HHV-8 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 geographical 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 and genital tract secretions. Taken together, these findings lead to the recognition that saliva is the major mode of transmission to children in areas where HHV-8 infection is endemic, whereas sexual contact is a source of infection among adults in low-prevalence areas. Other less common routes of HHV-8 transmission include blood transfusion, bone marrow transplantation, and solid organ transplantation. Vertical transmission may occur in regions where HHV-8 is highly endemic, but the risk appears low.

Pathology/Pathogenesis

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 p53 and retinoblastoma protein, induce the expression of pro-angiogenesis factors vascular endothelial growth factor (VEGF) A and VEGF receptor-2, and lead to upregulation of the human mammalian target of rapamycin (mTOR) pathway, which is instrumental in the control of cell growth and metabolism. HHV-8 also encodes a homolog of human interleukin-6 (IL-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 (NF-κB). All of these proteins may be potential targets for therapeutic intervention.

Clinical Manifestations

Although subclinical infection appears to be common, symptomatic primary HHV-8 infection has been described in immunocompetent children. Patients commonly had fever and a maculopapular rash or a mononucleosis-like syndrome, with full recovery the rule.

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). Post-transplantation KS and AIDS-related KS are the most severe forms, with disseminated lesions often in the gastrointestinal tract and lungs in addition to the skin.

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.

Diagnosis

Serologic assays, including immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Western blot, are the primary methods of diagnosing infection with HHV-8. However, testing has limited sensitivity, specificity, and reproducibility and is primarily a research tool. 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 the HHV-8 genome in tissue samples.

Treatment

Treatment for KS, PEL, and multicentric Castleman disease is multifaceted and includes attempts to control malignant proliferations with traditional radiotherapy and chemotherapeutic regimens as well as agents aimed at specific cellular pathways targeted by HHV-8 proteins. Therapies such as rapamycin to block the mTOR pathway, proteosome inhibitors aimed at decreasing the activation of NF-κB, and monoclonal antibodies to block the IL-6 receptor or CD20 are under investigation. Additionally, in patients with HIV infection, highly active antiretroviral treatment (HAART) is a mainstay of therapy for the treatment of HHV-8–related disease. Oral valganciclovir decreases both the quantity and frequency of detection of HHV-8 in saliva, suggesting that specific antiviral therapy might also play a role in treatment or prevention of diseases due to HHV-8.