Mosaicism of HTLV-1 5′ LTR CpG methylation in the absence of malignancy

Viral expression varies widely between untransformed HTLV-1 positive clones derived from infected individuals without malignancy. Here we show that, in the absence of malignancy, 68% of HTLV-1 positive clones carry deleted (10%) or methylated (58%) 5′ LTR. These changes were found to contribute to the fluctuation of viral expression between clones. 5′ LTR deletions strongly impaired tax expression and thereby clonal expansion, telomere homeostasis, and genetic instability. The effects of CpG methylation on viral transcription were qualitatively and quantitatively different from those of LTR deletions and preserved the preleukemic features of HTLV-1+CD4+ clones. 5′ LTR methylation varied not only between clones but also between cells belonging to the same clones, between distinct integrated sequences within the same cells, and between CpG dyads along the 5′ LTR. Such distributions suggest that a dynamic methylation spectrum might help sustain persistent infection.