Molecular mimicry is implicated in the pathogenesis of autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis (MS). Cellular and antibody-mediated immune responses to shared viral-host antigens have been associated with the development of disease in these patients. Patients infected with human T-lymphotropic virus type I (HTLV-I) develop HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disorder of the central nervous system (CNS) that resembles some forms of MS. Damage to neuronal processes in the CNS of HAM/TSP patients is associated with an activated cellular and antibody-mediated immune response. In this study, IgG isolated from HAM/TSP patients was immunoreactive with uninfected neurons and this reactivity was HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and cell lines but not nonneuronal cells. Neuronal western blots showed IgG reactivity with a single 33-kd band in all HAM/TSP patients tested. By contrast, no neuron-specific IgG reactivity could be demonstrated from HTLV-I seronegative controls and, more important, from HTLV-I seropositive, neurologically asymptomatic individuals. Both immunocytochemical staining and western blot reactivity were abolished by preincubating HAM/TSP IgG with HTLV-I protein lysate but not by control proteins. Staining of CNS tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax protein or preincubation of CNS tissue with the monoclonal antibody to HTLV-I tax abrogated the immunocytochemical and western blot reactivity of HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP brain but not in normal brain. These data indicate that HAM/TSP patients develop an antibody response that targets uninfected neurons, yet reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune reactivity to the CNS, the damaged target organ in HAM/TSP.

Interactions between the Human T-cell leukemia virus type I (HTLV-I) gene product p13(II) and cellular proteins were investigated using the yeast two-hybrid system. Variant forms of p13(II) were derived from two HTLV-I molecular clones, K30p and K34p, that differ in both virus production and in vivo and in vitro infectivity. Two nucleotide differences between the p13 from K30p (p13K30) and K34p (p13K34) result in a Trp-Arg substitution at amino acid 17 and the truncation of the 25 carboxyl-terminal residues of p13K34. A cDNA library from an HTLV-I-infected rabbit T-cell line was screened with p13K30 and p13K34 as bait. Products of two cDNA clones, C44 and C254, interacted with p13K34 but not with p13K30. Interactions were further confirmed using the GST-fusion protein coprecipitation assay. Sequence analysis of C44 and C254 cDNA clones revealed similarities to members of the nucleoside monophosphate kinase superfamily and actin-binding protein 280, respectively. Further analysis of the function of these two proteins and the consequence of their interaction with p13 may help elucidate a role for p13 in virus production, infectivity, or the pathogenesis of HTLV-I.