Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8), is an oncovirus belonging to the herpesviridae family, capable of causing cancer. KSHV establishes a lifelong infection, remaining dormant within host cells. While often asymptomatic in healthy individuals, it poses a risk to those with weakened immune systems. The virus was first identified in 1994 in lesions from AIDS patients, establishing its link to Kaposi’s sarcoma.
Associated Diseases and Conditions
KSHV is the causative agent for several distinct conditions, primarily affecting individuals with compromised immune systems.
Kaposi’s Sarcoma (KS)
Kaposi’s Sarcoma (KS) is a cancer that originates from the cells lining lymph or blood vessels. It presents as purplish, reddish, or brown patches, plaques, or nodules on the skin, mouth, lymph nodes, or internal organs. Lesions are often painless initially, but can grow into raised bumps or form open wounds. Depending on its specific type, KS may worsen gradually or rapidly.
Several types of Kaposi’s Sarcoma exist, each with distinct epidemiological patterns. Epidemic KS (AIDS-associated KS) is the most common form, occurring in individuals with HIV/AIDS and often defining AIDS. Classic KS affects older men of Mediterranean, Eastern European, or Ashkenazi Jewish descent, presenting as slow-growing lesions on the legs and feet. Endemic KS is prevalent in sub-Saharan Africa, where it can be aggressive in children, affecting lymph nodes, while in adults it resembles classic KS. Additionally, iatrogenic KS can develop in organ transplant recipients due to immunosuppressive medications.
Primary Effusion Lymphoma (PEL)
Primary Effusion Lymphoma (PEL) is a rare and aggressive type of non-Hodgkin lymphoma associated with KSHV. This lymphoma is characterized by the accumulation of cancerous fluid in body cavities such as the chest (pleural effusion), abdomen (peritoneal effusion), or around the heart (pericardial effusion), often without forming a solid tumor mass. Symptoms depend on the affected cavity, including shortness of breath for pleural or pericardial involvement, or abdominal distension for peritoneal disease. Patients commonly experience systemic symptoms like fever, weight loss, and night sweats.
Multicentric Castleman Disease (MCD)
Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder where multiple lymph nodes become enlarged and overactive due to KSHV infection. While not technically a cancer, it involves overproduction of immune cells (particularly plasmablasts) and signaling proteins called cytokines, which cause widespread inflammation and can increase the risk of lymphoma and Kaposi’s Sarcoma. Symptoms include persistent fever, fatigue, unintentional weight loss, muscle aches, and generalized lymphadenopathy (enlarged lymph nodes). Patients may also experience an enlarged spleen or liver, and fluid retention.
Transmission and Risk Factors
KSHV transmission occurs through direct contact with infected bodily fluids, primarily saliva. Deep kissing is a recognized mode of transmission. Sexual transmission is also significant, particularly among men who have sex with men.
Less common routes of KSHV transmission include organ transplantation and blood transfusions. However, the risk from blood transfusions has decreased due to improved screening practices. Vertical transmission from mother to child through saliva can also occur in regions where the virus is highly prevalent.
The development of KSHV-associated diseases is linked to a weakened immune system. Individuals with HIV/AIDS are a primary risk group, as their compromised immune function allows the virus to reactivate and cause disease. Organ transplant recipients, who receive immunosuppressive drugs, are also at an elevated risk.
The elderly also face an increased risk, as immune function declines with age. Geographic prevalence plays a role, with KSHV more common in specific parts of the world. High rates of infection are observed in sub-Saharan Africa and the Mediterranean region, indicating genetic and environmental factors may contribute to disease susceptibility.
The Viral Lifecycle and Pathogenesis
KSHV establishes a lifelong infection within its host, characterized by two phases: latency and the lytic cycle. The latent phase is the default state, where the virus remains dormant within infected host cells without producing new virus particles. During this phase, viral DNA persists within cells, primarily B cells and endothelial cells, without causing overt symptoms.
The lytic cycle is the active phase of the virus, where it replicates and produces new infectious particles, often leading to host cell death. While latency is the usual state, triggers such as a weakened immune system or specific cellular signals can induce the virus to switch from latency to the lytic cycle. This shift is crucial for viral spread but also contributes to the development of KSHV-associated diseases.
During latency, KSHV expresses viral proteins instrumental in oncogenesis. These latency-associated proteins include Latency-Associated Nuclear Antigen (LANA-1), viral FLICE inhibitory protein (v-FLIP), and viral cyclin. These proteins hijack host cell pathways to promote uncontrolled cell growth and division, a hallmark of cancer. LANA-1, for instance, helps maintain the viral genome within the host cell and interferes with tumor suppressor proteins that regulate cell proliferation.
KSHV proteins prevent apoptosis (natural cell death), allowing infected cells to survive and accumulate. Viral cyclin, for example, mimics human cyclins to promote cell cycle progression, while v-FLIP inhibits apoptotic pathways. Viral proteins also stimulate angiogenesis (new blood vessel formation), necessary for tumor growth by supplying nutrients and oxygen. KSHV proteins help infected cells evade immune detection, allowing abnormal cells to persist and proliferate, leading to tumors like Kaposi’s sarcoma and lymphomas.
Diagnosis and Management
Diagnosis of KSHV infection and its associated diseases involves a two-pronged approach. The initial step includes blood tests, specifically serology, to detect antibodies against KSHV. The presence of these antibodies indicates prior exposure to the virus, but does not confirm active disease or a specific KSHV-associated condition.
For a definitive diagnosis of diseases like Kaposi’s Sarcoma, Primary Effusion Lymphoma, or Multicentric Castleman Disease, confirming viral presence within diseased tissue is necessary. This is achieved through a biopsy, where a tissue sample is taken from the affected area. Laboratory techniques such as polymerase chain reaction (PCR) are used on the biopsy sample to identify KSHV DNA, confirming viral involvement.
There is no cure for KSHV infection; management focuses on controlling and treating associated diseases. A primary strategy involves restoring or improving immune function. For individuals with HIV/AIDS, highly active antiretroviral therapy (HAART) is a cornerstone. HAART can improve immune suppression, often leading to shrinkage or disappearance of Kaposi’s Sarcoma lesions.
For patients not responding to immune restoration or in severe cases, other treatments are employed. These include chemotherapy (drugs to kill cancer cells) and radiation therapy (high-energy rays to destroy tumor cells). Targeted therapies, focusing on specific molecules involved in cancer growth and spread, are also utilized to control the progression of KSHV-associated cancers.