Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2

Abstract

HTLV-1 and HTLV-2 are highly related complex retroviruses that have been studied intensely for nearly three decades because of their association with neoplasia, neuropathology, and/or their capacity to transform primary human T lymphocytes. The study of HTLV also represents an attractive model that has allowed investigators to dissect the mechanism of various cellular processes, several of which may be critical steps in HTLV-mediated pathogenesis. Both HTLV-1 and HTLV-2 can efficiently immortalize and transform T lymphocytes in cell culture and persist in infected individuals or experimental animals. However, the clinical manifestations of these two viruses differ significantly. HTLV-1 is associated with adult T-cell leukemia (ATL) and a variety of immune-mediated disorders including the chronic neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast, HTLV-2 is much less pathogenic with reports of only a few cases of variant hairy cell leukemia and neurological disease associated with infection. The limited number of individuals shown to harbor HTLV-2 in association with specific diseases has, to date, precluded convincing epidemiological demonstration of a definitive etiologic role of HTLV-2 in human disease. Therefore, it has become clear that comparative studies designed to elucidate the mechanisms by which HTLV-1 and HTLV-2 determine distinct outcomes are likely to provide fundamental insights into the initiation of multistep leukemogenesis.

Figure 1

Genome organization of HTLV-1 and HTLV-2. HTLV-1 and HTLV-2 proviral genomes and the open reading frames are shown. Highlights the HTLV-2 mRNA species, including at least seven mRNAs. The genomic unspliced mRNA encodes the Gag, Pol, and Pro proteins. In addition to the unspliced species, three singly spliced mRNAs contain exon 1 (nt 1–134) linked to splice acceptor sites at 4729 (Env), 6629 (p28, p22/p20), or 6899 (p28, p22/p20). The major doubly spliced mRNA encodes Tax/Rex and contains exons 1 and 2 (nt 4729–4868) linked to a splice acceptor at position 6899. The other doubly spliced mRNAs contain exons 1 and 2 linked to a splice acceptor at 6629 or 6491; their protein products are less characterized

Figure 2

Structural and functional domains of Tax-1 and Tax-2A. Specific domains, mutations and the transcriptional activation pathways interrupted are indicated