Human Herpesvirus 8 (HHV‑8), also known as Kaposi sarcoma‑associated herpesvirus (KSHV), is a gammaherpesvirus with an enveloped double‑stranded DNA genome. It infects endothelial cells and B lymphocytes and is etiologically linked to Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease.
Virology and Oncogenic Mechanisms
HHV‑8 has an icosahedral capsid surrounded by a tegument and an envelope containing glycoproteins that mediate entry via integrins and other receptors. Its genome (~165 kb) encodes not only the core herpesvirus replication machinery but also a suite of homologues of cellular genes that modulate signaling, apoptosis and immune responses. These include viral G‑protein‑coupled receptor (vGPCR), viral interleukin‑6 and viral cyclin D. Infection begins with lytic replication in endothelial cells or B cells, producing new virions. The virus then establishes latency, maintained by expression of a single predominant latent nuclear antigen (LANA) that tethers the viral episome to host chromosomes and regulates host gene expression. Latency‑associated transcripts also encode viral FLICE inhibitory protein (vFLIP) and viral cyclin, which promote cell survival and proliferation. Reactivation to the lytic cycle is controlled by the replication and transcription activator (RTA). The expression of viral oncogenes during latency and lytic replication contributes to transformation of endothelial cells into the spindle cells characteristic of Kaposi sarcoma.
Associated Diseases and Epidemiology
HHV‑8 is necessary but not sufficient for the development of Kaposi sarcoma, a vascular neoplasm characterized by violaceous skin or mucosal lesions composed of spindle cells and aberrant angiogenesis. Four epidemiologic forms of Kaposi sarcoma exist: classic, endemic (African), iatrogenic (immunosuppression‑associated) and epidemic (AIDS‑associated). Co‑infection with HIV dramatically increases the risk and severity of Kaposi sarcoma, as HIV Tat protein and immunosuppression enhance HHV‑8 replication and oncogenesis. Primary effusion lymphoma, an aggressive B‑cell lymphoma presenting as effusions in body cavities, and a subset of multicentric Castleman disease also require HHV‑8 infection. Transmission of HHV‑8 occurs through saliva, sexual contact and blood, with prevalence varying geographically; it is high in sub‑Saharan Africa and Mediterranean regions. Diagnosis involves PCR detection of viral DNA or immunohistochemistry for LANA in biopsied tissue. There is no specific antiviral therapy for latent HHV‑8; management of Kaposi sarcoma includes antiretroviral therapy for HIV, reduction of immunosuppression, chemotherapy and immune modulators. Prevention relies on controlling HIV infection and minimizing exposure. HHV‑8 distinguishes itself from other human herpesviruses through its repertoire of captured oncogenes and its role in vascular and lymphoid tumors. Understanding its biology has illuminated mechanisms of viral oncogenesis and informed treatment strategies for associated diseases. Related Terms: Kaposi sarcoma, primary effusion lymphoma, LANA, gammaherpesvirus, spindle cell