HHV-8

In 1994, Chang and coworkers discovered human herpesvirus 8 (HHV-8) as the etiologic agent of Kaposi's sarcoma (Dow D et al. 2014)

Human herpesvirus 8 (HHV-8) is the newest member of the human herpesvirus family. Like HHV-6, it is a worldwide herpesvirus that belongs to the family Herpesviridae, the subfamily Gammaherpesvirinae and the genus Rhadinovirus. The pathogen reservoir is only humans. As a member of the Herpesviridae family, the complex virus has a DNA genome of about 150Kb. It is helically arranged around a core consisting of proteins and is enclosed by a capsid. The capsid contains up to 12 glycoproteins.

HHV-8 a human carcinogenic virus: HHV-8 is one of the human carcinogenic viruses, together with the following viruses, which are responsible for 10-15% of all cancers worldwide:

• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Epstein-Barr virus (EBV)
• Human papilloma virus(HPV)
• Human T-lymphotropic virus 1

HHV-8 is a gamma herpes virus and is most commonly seen in people of Arab, Jewish, African, Turkish, Greek or Italian descent. Only 0-5% of adults are positive for HHV-8 antibodies. However, approximately 12% of transplant recipients develop HHV-8 antibodies.

The mode of transmission of human herpesvirus 8 remains elusive. With the discovery of HHV-8 and the increase in Kaposi's sarcoma (KS) in men who have sex with men, it was suspected that HHV-8 is a sexually transmitted virus (Martin JN et al 1998, Hof H et al 2019). This assumption has been strengthened by the detection of HHV-8 DNA in semen. However, a study investigating the sites of HHV-8 shedding also found virus in vaginal (2.3%) and cervical secretions (4%), but the highest prevalence was found in saliva (32%) and oral swabs (28%). These studies show that the oral mucosa is a primary site of viral shedding (Taylor MM et al (2004). The high HHV-8 seroprevalence in African children also suggests that transmission is likely via saliva exchange, similar to EBV. There is no clear evidence of fecal-oral transmission (Mayama S et al. (1998). In contrast, primary HHV-8 infection may occur after blood transfusion.

HHV-8 binds to integrin β-3. The virus is able to infect B cells, endothelial cells, macrophages and epithelial cells. The virus exists between a lytic and latent life cycle that allows the pathogen to alternate between active replication and dormant infection. The virus encodes a number of proteins and small RNAs that appear to help the virus evade the host immune response, allowing for lifelong persistence. Thus, the virus impairs host antigen presentation and T-cell activation. It induces secretion of IL-6, promoting proliferation of B cells, and angiogenic cytokines, stimulating VEGF expression.

Influence of HIV: The impact of HIV on HHV-8 disease is substantial, suggesting that HIV is a necessary cofactor for progression from HHV-8 infection to KS. In Zambia, nearly 20% of childhood cancers between 1987 and 1992 were KS compared to only 6% before 1986; nearly 60% of these KS tumors occurred in children younger than 5 years (Dow D et al. 2014).

HHV-8 is the viral agent of Kaposi's sarcoma, primary effusion lymphoma (a large B-cell lymphoma localized in the body cavities and characterized by pleural, peritoneal and pericardial effusions) and multicentric Castleman's lymphoma. These malignancies often occur in the context of immunosuppression. In addition to KS, HHV-8 is considered a possible trigger of hemophagocytic lymphohistiocytosis. Patients with primary immunodeficiency are also at increased risk for disseminated HHV-8 infection (Dow D et al. 2014). Primary infection in transplant recipients may present with fever, splenomegaly, rash, lymphoid hyperplasia, and pancytopenia.

To diagnose infection, seropositivity is usually determined using both an enzyme immunoassay to detect lytic proteins, usually ORF-65 and recombinant K8.1 proteins, and an immunofluorescence assay to detect LANA protein produced by ORF-73 and/or other lytic antigens. In general, these assays have a reported sensitivity and specificity between 50% and 95% (Dow D et al. 2014).

Molecular assays are also available but are not commonly used. The standard polymerase chain reaction can detect virus in both the lytic and latent states, but does not differentiate between the two. Copy numbers of human herpesvirus 8 may be low and the virus may be detected sporadically in tissue and blood. Detection of HHV-8 viremia in an HIV-positive person is a risk factor for progression to KS disease.

• The seroprevalence of human herpesvirus 8 varies widely throughout the world. Geographic areas are often divided into three groups: low HHV-8 seroprevalence (<5%), traditionally found in North America, much of Europe, and Asia
• medium seroprevalence (5-20%), which includes the Mediterranean region, Eastern Europe, the Caribbean, and the Middle East
• high seroprevalence (>50%), which includes much of Africa and regions of the Brazilian Amazon (Caterino-de-Araujo A et al.2010, Chatlynne LG et al. 1999, Mbulaiteye SM et al. 2003).

The"KS belt" is a region in equatorial Africa where, even before HIV, the progression of HHV-8 to endemic KS was particularly high (Dollard SC et al. 2010). The belt extends from the coast of Cameroon through the northeast of the Democratic Republic of Congo and down the Rift Valley to Malawi, including Uganda, Tanzania, and Zambia. In this area, KS is among the most common pediatric cancers, often second only to Burkitt's lymphoma (Gantt S et al. 2010).

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