Comparative molecular analysis of HTLV-I proviral DNA in HTLV-I infected members of a family with a discordant HTLV-I-associated myelopathy in monozygotic twins
S. Nakane et al., Comparative molecular analysis of HTLV-I proviral DNA in HTLV-I infected members of a family with a discordant HTLV-I-associated myelopathy in monozygotic twins, J NEUROVIRO, 6(4), 2000, pp. 275-283
In order to elucidate the underlying mechanisms of a discordant case with H
TLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in monoz
ygotic twins, we investigated HTLV-I fax sequences of 10-18 polymerase chai
n reaction-based clones each derived from peripheral blood mononuclear cell
s of the twins as well as their infected mother and an elder brother who al
so suffered from HAM/TSP. Sequence comparison revealed that three of the in
fected individuals including a twin with HAM/TSP shared the consensus tax s
equence identical to the reference, ATK-1, but that of another healthy twin
was different at five nucleotide positions including three nonsynonymous c
hanges from ATK-1. This finding strongly suggested that different HTLV-I st
rains infected the monozygotic twins and the difference in infected provira
l sequences determined the discordant clinical outcomes. Transfection and s
ubsequent reporter assays failed to show a significant difference in transa
ctivation activity on HTLV-I LTR and NF-kappa B elements between the produc
ts of the two sequences. Two HAM/TSP patients (a twin and elder brother) am
ong three members infected with the ATK-1 type virus shared a paternal HLA
allele which was absent in the healthy individual (mother). Genetic analysi
s of sequence variation in the fox sequences of the discordant twins showed
that the Dn/Ds ratio was high in the healthy twin but low in the twin with
HAM/TSP, implying the presence of more intense selection forces in the car
rier. Our findings strongly suggested that a particular combination of HTLV
-I strains with an HLA genotype would be a risk for HAM/TSP.