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.
In order to elucidate the underlying mechanisms of a discordant case with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in monozygotic twins, we investigated HTLV-I tax sequences of 10 - 18 polymerase chain reaction-based clones each derived from peripheral blood mononuclear cells of the twins as well as their infected mother and an elder brother who also suffered from HAM/TSP. Sequence comparison revealed that three of the infected individuals including a twin with HAM/TSP shared the consensus tax sequence identical to the reference, ATK-1, but that of another healthy twin was different at five nucleotide positions including three nonsynonymous changes from ATK-1. This finding strongly suggested that different HTLV-I strains infected the monozygotic twins and the difference in infected proviral sequences determined the discordant clinical outcomes. Transfection and subsequent reporter assays failed to show a significant difference in transactivation activity on HTLV-I LTR and NF-kappaB elements between the products of the two sequences. Two HAM/TSP patients (a twin and elder brother) among three members infected with the ATK-1 type virus shared a paternal HLA allele which was absent in the healthy individual (mother). Genetic analysis of sequence variation in the tax 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 carrier. Our findings strongly suggested that a particular combination of HTLV-I strains with an HLA genotype would be a risk for HAM/TSP.
Nakane
S
S
The First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Shirabe
S
S
Moriuchi
R
R
Mizokami
A
A
Furuya
T
T
Nishiura
Y
Y
Okazaki
S
S
Yoshizuka
N
N
Suzuki
Y
Y
Nakamura
T
T
Katamine
S
S
Gojobori
T
T
Eguchi
K
K
D003001:Cloning, Molecular; D016384:Consensus Sequence; D004200:Diseases in Twins; D005260:Female; D016356:Gene Products, tax / Q000235:genetics; D005814:Genes, Viral; D014644:Genetic Variation; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D015493:Paraparesis, Tropical Spastic / Q000175:diagnosis / Q000821:virology*; D010375:Pedigree; D011533:Proviruses / Q000235:genetics* / Q000302:isolation & purification; D012307:Risk Factors; D012703:Serotyping; D014430:Twins, Monozygotic; D019562:Viral Load
D016356:Gene Products, tax