Mechanism of leukemogenesis by human T-cell leukemia virus types I and II: role of the lor gene.

The human T-cell leukemia (HTLV) family of viruses now include two groups of transforming viruses (HTLV-I and HTLV-II) and one group of viruses with immunosuppressive activity but no apparent transforming ability (HTLV-III). Nucleotide sequence analysis of an HTLV-I provirus by Seiki et al [Proc Natl Acad Sci USA 1982: 6899-902] has revealed a distinct region of the genome located between env and the long terminal repeat sequences (LTR). Analysis of a variant of HTLV-I, called HTLV-Ib, which retains transforming ability, revealed a deletion in the 5' portion of this sequence that indicates that this portion of the sequence probably does not play an essential role in transformation. Hybridizations at varying stringencies show that at least a portion of this additional region of HTLV-I and -II is more highly conserved than most other regions of the genome. The DNA sequence of this HTLV-II region localizes the area of homology within the 1,000 base pairs just upstream of the LTR; the remainder of the region is not conserved. The conserved region includes a long open reading frame, is denoted lor, and has the coding capacity for a protein of at least 38 kilodaltons (kd). Studies of the transcriptional activity of the LTR sequences show that the rate of LTR-directed transcription is greatly augmented in HTLV-infected cells, a phenomenon called trans-acting transcriptional regulation. It is suggested that transformation of lymphocytes by HTLV-I or -II is mediated by action of HTLV-encoded trans-acting transcription factors on cellular genes that control the replication of lymphocytes.