History

In 1872, M. Kaposi, a Hungarian dermatologist, described a pigmented angiosarcoma, now called 'classic' or sporadic Kaposi sarcoma (KS), that mainly affected skin on the lower limbs, and was most prominent in elderly men of Mediterranean and eastern European origin. KS was also an African problem. In the 1960s and 1970s, the frequency and distribution of KS altered, and in many cases could be related to transplant therapies in other parts of the world. Whereas modest increases in KS were being reported in various countries prior to the onset of the syndromes now covered under the generic name AIDS, its frequency and epidemiology were drastically influenced by the spread of this virus. Over the past decade or so, although the histo-pathological presentations of all types of KS are identical, this malignancy has been generally subclassified into classic (sporadic), endemic (African), epidemic (AIDS related) and immunosuppression-associated (transplant) types, to reflect its origin. From being a comparatively rare form of cancer, KS is now fairly common in certain parts of the world. Exactly how common, however, is a controversial topic. The epidemiology of this cancer, and particularly the fact that in the early days it was the most common tumour in AIDS patients, with 15-20% of them developing KS, suggested that this disease might have an infectious aetiology (IARC, 1997). Thus, an active search to find such an agent was initiated.

The history of the discovery of KSHV is different from that of EBV, the human virus it most resembles, and owes much to the development of molecular biological methodologies. One of these in particular, called representational difference analysis (RDA), was used by a group in the USA, working with the husband and wife team Moore and Chang (Chang et al., 1994), in their search for a KS infectious agent. RDA consists of generating genomic representative entities from diseased and normal tissues, preferably from the same individual, using PCR amplification. These are stably associated with priming PCR sequences and hybridized to an excess of representative, nonligated amplified sequence, with no attached primers, from normal tissue. Following this procedure, only unique sequences found in the diseased tissues will contain priming sequences on both strands, which allows them to be substrates for subsequent PCR reactions. Repeating such a process enriches the sample for unique sequences.

Lytic antigen epitopes

Human DNA Tumour Viruses 63 Latent antigen epitopes

LLWAARPRL (HLA A2)

TLFIGSHVV (HLA A2) LMIIPLINV (HLA A2) SLVIVTTFV (HLA A2)

DYCNVLNKEF (HLA A24) LVSDYCNVLNKEFTA (HLA B18) ATIGTAMYK (HLA A11) RALIKTLPRASYSSH (HLA A2) KHSRVRAYTYSKVLG (HLA A3) QKEEAAICGQMDLSH (HLA B61)

RAKFKQLL (HLA B8) RKCCRAKFKQLLQHYR (HLA C6)

VLQWASLAV (HLA A2)

KDTWLDARM (HLA ?) GLCTLVAML (HLA A2)

YRSGIIAVV (HLA C6)

AGLTLSLLVICSYLFISRG (HLA DR2) TVVLRYHLLEEI (HLA DR4)

BARF0

gp85

BRLF1 BZLF1

gp350 BMLF1 BMRF1

BHRF1

EBV genome

Figure 10 Schematic distribution of HLA class I and class II restricted cytotoxic T lymphocyte epitopes with EBV latent and lytic antigens, at the peptide level. BARFO, the largest ORF in the CST transcripts is given here as a lytic function, although it is also expressed during the latent cycle. (Adapted from Khanna et al., 1999.)

These can then be purified and their sequences determined. By RDA, using tissues from AIDS-associated KS, Chang et al. (1994) identified sequences that were homologous with, but distinct from, other members of the

7-herpesvirus family, most notably EBV and the onco-genic primate virus, herpesvirus saimiri. They correctly concluded, as was subsequently shown, that this work was consistent with the presence of a new human herpesvirus in KS lesions. Interestingly, the homologies they identified were with EBV late viral genes (in BDLF1 and BcLFl, see EBV section).

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