HTLV-1 infection is linked with a neurodegenerative disorder HTLV1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of the singly or doubly spliced ORF-I cDNA of HTLV-1 results in the production of the 12 kD and 8 kD protein isoforms. The uncleaved 12 kD form resides in the ER and affects MHC-I and IL-2R. The cleaved 8 kD form traffi cs to the cell surface, is recruited to the immunological synapse upon T-Cell Receptor (TCR) stimulation decreasing TCR signaling and viral replication. Genetic analysis of ORF-I from ex vivo samples of HTLV-1 infected individuals reveals amino acid substitutions that affect its proteolytic cleavage, suggesting that ER or membrane associated functions of ORF-I may contribute to the persistence of HTLV-1 infected T-cells in the host. To investigate a putative relationship between ORF-I forms and provirus level, the best predictor of disease development, we measured the provirus level in the blood and linked it with the presence of ORF-I isoforms. The provirus levels ranged from 0.2 to 165 copies of proviral DNA per 106 PBMCs. DNA sequencing and reverse genetics revealed mutations at/in the vicinity of both cleavage sites within ORF-I. A rare mutation found at position 26 in ORF-I resulted mainly in the presence of the 8 kD isoform. Importantly, patients with this mutation had signifi cantly lower virus that those that carried either 12 kD isoform or both forms, and with one exception they belonged to a healthy carrier group.
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