The genome of the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) was mapped with cosmid and phage genomic libraries from the BC-1 cell line. Its nucleotide sequence was determined except for a 3-kb region at the right end of the genome that was refractory to cloning. The BC-1 KSHV genome consists of a 140.5-kb-long unique coding region flanked by multiple G + C-rich 801-bp terminal repeat sequences. A genomic duplication that apparently arose in the parental tumor is present in this cell culture-derived strain. At least 81 ORFs, including 66 with homology to herpesvirus saimiri ORFs, and 5 internal repeat regions are present in the long unique region. The virus encodes homologs to complement-binding proteins, three cytokines (two macrophage inflammatory proteins and interleukin 6), dihydrofolate reductase, bcl-2, interferon regulatory factors, interleukin 8 receptor, neural cell adhesion molecule-like adhesin, and a D-type cyclin, as well as viral structural and metabolic proteins. Terminal repeat analysis of virus DNA from a KS lesion suggests a monoclonal expansion of KSHV in the KS tumor.

https://www.pnas.org/content/pnas/93/25/14862.full.pdf

Nucleotide sequence of the kaposi sarcoma-associated herpesvirus (hhv8)

In 1872, Moritz Kaposi, a Hungarian dermatologist, described five men with aggressive “idiopathic multiple pigmented sarcomas of the skin.”1 One patient died of gastrointestinal bleeding 15 months after the initial appearance of the skin lesions, and an autopsy showed visceral lesions in the lungs and the gastrointestinal tract. Subsequently, other investigators described four clinical variants of Kaposi's sarcoma that had identical histologic features but developed in specific populations and had different sites of involvement and rates of progression (Table 1). In the light of recent discoveries regarding the viral pathogenesis of Kaposi's sarcoma, these variants most likely represent different manifestations . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM200004063421407?listPDF=true

Kaposi's Sarcoma

Four virus proteins similar to two human macrophage inflammatory protein (MIP) chemokines, interleukin-6 (IL-6), and interferon regulatory factor (IRF) are encoded by the Kaposi's sarcoma-associated herpesvirus (KSHV) genome. vIL-6 was functional in B9 proliferation assays and primarily expressed in KSHV-infected hematopoietic cells rather than KS lesions. HIV-1 transmission studies showed that vMIP-I is similar to human MIP chemokines in its ability to inhibit replication of HIV-1 strains dependent on the CCR5 co-receptor. These viral genes may form part of the response to host defenses contributing to virus-induced neoplasia and may have relevance to KSHV and HIV-I interactions.

https://science.sciencemag.org/content/sci/274/5293/1739.full.pdf

Molecular Mimicry of Human Cytokine and Cytokine Response Pathway Genes by KSHV

Infections may be responsible for over 15% of all malignancies worldwide. Important mechanisms by which infectious agents may induce carcinogenesis include the production of chronic inflammation, the transformation of cells by insertion of oncogenes and inhibition of tumour suppressors, and the induction of immunosuppression. Common characteristics shared by infectious agents linked to malignancies are that they are persistent in the host, often highly prevalent in the host population and induce cancer after a long latency. The associations between a selection of infectious agents and malignancies are covered in detail.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2796.2000.00742.x

Infections as a major preventable cause of human cancer

Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.

Kaposi's sarcoma and its associated herpesvirus

A major controversy regarding Kaposi's sarcoma–associated herpesvirus (KSHV or HHV8)1,2 is whether or not it is a ubiquitous infection of humans3,4. Immunoassays based on KSHV– and Epstein–Barr virus (EBV)–coinfected cell lines show that most US AIDS–KS patients have specific antibodies to KSHV–related antigens2,5,6. We have developed a sensitive indirect immunofluorescence assay (IFA) based on an EBV–negative, KSHV–infected cell line, BCP–1. When we used this IFA assay, KSHV–related antibodies were found in 71–88% of serum samples from US, Italian and Ugandan AIDS–KS patients, as well as all serum samples examined from HIV–seronegative KS patients. Although none of the US blood donors examined were KSHV seropositive by IFA, intermediate and high seroprevalence rates were found in Italian and Ugandan control populations. Antibody kinetics showed that more than half of the AIDS–KS patients who were examined IgG–seroconverted before KS development, and antibody levels did not decline after seroconversion. For these patients, seropositivity rates increased linearly with time, suggesting that the rate of infection was constant and that the risk of developing KS once infected with KSHV is not highly dependent on the duration of infection. These data strongly suggest that KSHV is not ubiquitous in most populations and that the virus may be under strict immunologic control in healthy KSHV–infected persons.

Ming Li

Papers

KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma.