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Review
. 2003 Jun;67(2):175-212, table of contents.
doi: 10.1128/MMBR.67.2.175-212.2003.

Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis

Lyubomir A Dourmishev  1 , Assen L Dourmishev, Diana Palmeri, Robert A Schwartz, David M Lukac
Affiliations
Review

Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis

Lyubomir A Dourmishev et al. Microbiol Mol Biol Rev. 2003 Jun.

Abstract

Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection.

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Figures

FIG. 1.
FIG. 1.
ORF map of the KSHV genome. A linear representation of the KSHV genome, showing the position of the ORFs as published in references , , , , is shown. Each ORF is represented by an arrow pointing in the direction in which it is expressed; ORFs are displayed linearly in two groups based on leftward or rightward direction. Approximate nucleotide positions are indicated in kilobases in the scale at top, as in reference . The expression kinetics of each ORF in PEL models of latency and reactivation are indicated by the fill of each arrow, as shown in the figure: latent (65, 122, 134, 156, 184, 431, 444, 483), IE (430, 448, 487, 489, 542), and lytic <24 h postinduction (hpi) and >24 h postinduction (236, 393) are all shown. An asterisk above an ORF indicates that at least one transcript encoding the ORF is spliced (either removing part of the ORF or introducing additional exons from outside the ORF). ORFs with published functions are indicated by bold lettering, and their respective functions are shown (see the text for relevant references). The nomenclature of each ORF follows that of reference and other references in the text. CBP, complement binding protein; DHFR, dihydrofolate reductase; TK, thymidine kinase; PF, processivity factor; UDG, uracil-DNA glycosylase; RR, ribonucleotide reductase; other abbreviations are defined in the text.
FIG. 1.
FIG. 1.
ORF map of the KSHV genome. A linear representation of the KSHV genome, showing the position of the ORFs as published in references , , , , is shown. Each ORF is represented by an arrow pointing in the direction in which it is expressed; ORFs are displayed linearly in two groups based on leftward or rightward direction. Approximate nucleotide positions are indicated in kilobases in the scale at top, as in reference . The expression kinetics of each ORF in PEL models of latency and reactivation are indicated by the fill of each arrow, as shown in the figure: latent (65, 122, 134, 156, 184, 431, 444, 483), IE (430, 448, 487, 489, 542), and lytic <24 h postinduction (hpi) and >24 h postinduction (236, 393) are all shown. An asterisk above an ORF indicates that at least one transcript encoding the ORF is spliced (either removing part of the ORF or introducing additional exons from outside the ORF). ORFs with published functions are indicated by bold lettering, and their respective functions are shown (see the text for relevant references). The nomenclature of each ORF follows that of reference and other references in the text. CBP, complement binding protein; DHFR, dihydrofolate reductase; TK, thymidine kinase; PF, processivity factor; UDG, uracil-DNA glycosylase; RR, ribonucleotide reductase; other abbreviations are defined in the text.
FIG. 1.
FIG. 1.
ORF map of the KSHV genome. A linear representation of the KSHV genome, showing the position of the ORFs as published in references , , , , is shown. Each ORF is represented by an arrow pointing in the direction in which it is expressed; ORFs are displayed linearly in two groups based on leftward or rightward direction. Approximate nucleotide positions are indicated in kilobases in the scale at top, as in reference . The expression kinetics of each ORF in PEL models of latency and reactivation are indicated by the fill of each arrow, as shown in the figure: latent (65, 122, 134, 156, 184, 431, 444, 483), IE (430, 448, 487, 489, 542), and lytic <24 h postinduction (hpi) and >24 h postinduction (236, 393) are all shown. An asterisk above an ORF indicates that at least one transcript encoding the ORF is spliced (either removing part of the ORF or introducing additional exons from outside the ORF). ORFs with published functions are indicated by bold lettering, and their respective functions are shown (see the text for relevant references). The nomenclature of each ORF follows that of reference and other references in the text. CBP, complement binding protein; DHFR, dihydrofolate reductase; TK, thymidine kinase; PF, processivity factor; UDG, uracil-DNA glycosylase; RR, ribonucleotide reductase; other abbreviations are defined in the text.
FIG. 2.
FIG. 2.
Primary structure-function map of KSHV ORF73/LANA-1. This schematic shows a linear representation of the amino acid content and predicted structural motifs of the LANA-1 protein. The amino acid numbering is as published in reference and corresponds to the virus from BC-1 cells. The internal repeat domain (IRD) is shown by the bracket, as in reference , and is described in the text. The approximate position of each functional domain is shown by a black bar, corresponding to the function shown in the column on the right (see the text for references). No amino acid boundaries are indicated for the functional domains, since functional mapping has used different isolates of LANA-1 that are variable in size. Abbreviations: DE, aspartic acid/glutamic acid rich; Q, glutamine, LZ, putative leucine zipper; QE, glutamine/glutamic acid rich.
FIG. 3.
FIG. 3.
Primary structure-function map of KSHV ORF50/Rta protein. This schematic shows a linear representation of the amino acid content and predicted structural motifs of the ORF50/Rta protein. The amino acid numbering is as published in reference . The approximate position of each functional domain is shown by a black bar, with amino acid boundaries indicated by numbers, corresponding to the function shown in the column on the right (see the text for references). Abbreviations: +++, basic amino acid rich; LZ, putative leucine zipper; ST, serine/threonine-rich; hyd/DE/hyd, repeats of hydrophobic and acidic amino acids, as in reference and described in the text.
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