LACK OF HTLV-I TAX BINDING MOTIFS IN HLA CLASS I MOLECULES IS ASSOCIATED WITH RISK OF ATL

Abstract

P078 HTLV-I causes ATL and HAM/TSP where HTLV-I Tax oncoprotein plays a key role for the leukemogenesis and the neuropathogenesis. However, it is unknown why one species of HTLV-I Tax oncoprotein causes two independent diseases of ATL and HAM/TSP. To explore the host factor determining the risk of ATL and HAM/TSP among HTLV-I carriers from southern Kyushu, we analysed HLA alleles of ATL and HAM/TSP as well as asymptomatic HTLV-I carriers (AC) and their peptide binding repertoire to recognize HTLV-I Tax and Env peptides using 165 synthetic peptides and in vitro CTL response in 40 donors of the known HLA class I alleles. ATL patients were characterized by three alleles of HLA class I (HLA-A*26, B*4002 and B*4006) while HAM/TSP was characterized by two alleles of HLA class I (HLA-A*24 and B*07) as compared to those of AC. ATL-associated HLA alleles lacked HTLV-I Tax peptide binding motifs and failed anti-Tax CD8+CTL induction. HAM/TSP-associated HLA alleles possessed numerous HTLV-I Tax peptide binding motifs and generated anti-Tax CD8+CTL. We further determined 17 HLA class I alleles other than those associated with ATL and HAM/TSP, and numerated the number of CTL epitopes for all HLA alleles of ATL, HAM/TSP and AC. Early onset cases of ATL(49.3 ± 8.9 years old) showed a significantly less number of Tax epitopes than late onset cases of ATL (59.1 ± 5.7 years old) while no significancant difference in the Env epitopes. These results suggested that risk of ATL may be determined by three distinct HLA class I alleles and number of Tax epitopes while HAM/TSP recognized a plenty of anti-Tax and anti-Env CTL epitopes.