Chimeric matrix proteins encoded by defective proviruses with large internal deletions in human T-cell leukemia virus type 1-infected humans

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spa stic paraparesis (HAM/TSP), and other diseases, The mechanisms of virus pat hogenesis are still obscure. The occurrence of defective proviruses in HTLV -1-infected cell lines and the peripheral blood mononuclear cells (PBMC) of infected individuals is a frequent feature of virus infection. We detected defective proviruses with large internal deletions in PBMC from ATLL and H AM/TSP patients and in asymptomatic HTLV-1 carriers. Seventeen PCR-amplifie d defective proviruses were sequenced, and three types of deletions were fo und. Besides truncated MA and the 5' end of the genome, truncated CA, trunc ated SU, and more frequently truncated TM linked to the pX region were dete cted. Reverse transcription-PCR analysis of PBMC from ATLL patients and asy mptomatic carriers also revealed RNA transcripts with large internal deleti ons. Analysis of two RT-PCR cDNA clones confirmed a Gag-TM-pX structure of the transcripts. Most defective proviruses contained numerous internal stop codons, but some were capable of coding for the truncated MA linked to a v ariable out-of-frame peptide. Cloned defective proviruses with long open re ading frames were subjected to in vitro transcription-translation followed by radioimmunoprecipitation, which showed expression of chimeric proteins b etween 8 and 12 kDa. Possible roles of defective proviruses and chimeric pr oteins are discussed, although there is no firm association with pathogenes is.