Increased seroreactivity to HERV-K10 peptides in patients with HTLV myelopathy

Abstract

BackgroundPreviously, we had shown that persons infected with human T-cell lymphoma leukemia virus 1 or 2 (HTLV-1 or 2) had an increased prevalence of antibodies to a peptide in the Pol protein of the retrovirus HERV-K10, homologous to a peptide in HTLV gp21 envelope protein. The prevalence rate was higher in those with myelopathy vs. non-myelopathy. We have now extended our observations to a cohort restricted to North America in whom the diagnosis of HTLV myelopathy was rigorously confirmed to also test for reactivity to another HERV-K10 peptide homologous to the HTLV p24 Gag protein.MethodsSera from 100 volunteer blood donors (VBD), 53 patients with large granular lymphocytic leukemia (LGLL), 74 subjects with HTLV-1 or 2 infection (58 non-myelopathy and 16 myelopathy) and 83 patients with multiple sclerosis (MS) were evaluated in ELISA assays using the above peptides.ResultsThe HTLV myelopathy patients had a statistically significant increased prevalence of antibodies to both HERV-K10 peptides (87.5%) vs. the VBD (0%), LGLL patients (0%), MS patients (4.8%), and the HTLV positive non-myelopathy subjects (5.2%).ConclusionThe data suggest that immuno-cross-reactivity to HERV-K10 peptides and/or transactivation of HERV-K10 expression by the HTLV Tax protein may be involved in the pathogenesis of HTLV-associated myelopathy/tropical spastic paraparesis and spastic ataxia.

Retroviral sero‐reactivity in LGL leukaemia patients and family members

“…These data are consistent with several scenarios; (a) LGL leukaemia patients and their close contacts are infected with an unknown retrovirus that shares epitopes in the transmembrane domain with HTLV‐1/2 and HIV‐1; (b) serological reactivity is to human endogenous retrovirus (HERV) proteins activated by exposure to a common environmental irritant or infection; or (c) serological reactivity is to cellular autoantigens with shared peptide domains to retroviral proteins. Although HERV‐K seroreactivity is reported in cancer patients, and RA patients are reported to have both HERV‐K antibodies and transcripts (Hahn et al , ; Freimanis et al , ), no antibody reactivity was detected to an epitope of HERV‐K10 Gag or Pol in 53 LGL leukaemia patients (Perzova et al , ). Given that up to 30% of LGL leukaemia patients also have RA (Lamy et al , ) and multiple lines of evidence suggest a common pathogenesis for LGL leukaemia and RA, which affects millions of people in the United States, further exploration of a possible role of HERVs in LGL leukaemia is warranted.…”

Morphological alterations in minor salivary glands of HTLV1+ patients: A pilot study

“…One of the proposed theories addresses the possibility that this sequence may belong to an endogenous retrovirus . Human endogenous retroviruses (HERVs) comprise 8 per cent of the human genoma, and although most of them are defective, their expression has been found in human tissues, including salivary glands, and to be especially associated with autoimmune and neurodegenerative diseases . Even though the role of these sequences has not been investigated within the context of SS pathogenesis, the fact that external agents (eg, tax gene) cause activation of HERVs—thus increasing their expression and leading to inflammatory responses—can be used to explain the lymphocytic reaction in minor salivary glands of HTLV‐1‐infected patients and perhaps also explain the difference in the lymphocytic population between SS group and HTLV‐1 group.…”

Human endogenous retroviruses in neurologic disease

“… Additionally, there are sporadic reports of increased HERV‐W RNA levels in post‐mortem brain from patients with Alzheimer's dementia , cross‐reactivity of HERV K peptides and HRES‐1 peptides with HTLV‐1 in HTLV‐1 myelopathia, and of RNA sequences encoded at several different HERV loci in the CSF of patients with sporadic Creutzfeldt–Jacob disease . Table is compiled from references in the text. …”

“…It tends to be overlooked that the original underlying rationale for testing a possible therapeutic efficacy of the widely used IFN-b in MS were its antiviral effects. Further, the antiretroviral activity of IFN-b has been established: for example, IFN-b1a therapy reduces the HTLV-I tax messenger RNA load and the frequency of potentially pathogenic HTLV-I-specific CD8(+) cells in patients with HAM/TSP (104), and IFN-b mediates suppression HERV-K HERV-W HIV-associated dementia (HAD) HERV-K HERV-H/F HERV-W Additionally, there are sporadic reports of increased HERV-W RNA levels in post-mortem brain from patients with Alzheimer's dementia (57), cross-reactivity of HERV K peptides (126) and HRES-1 peptides (15) with HTLV-1 in HTLV-1 myelopathia, and of RNA sequences encoded at several different HERV loci in the CSF of patients with sporadic Creutzfeldt-Jacob disease (127). Table 2 is compiled from references in the text.…”