Human T-cell leukemia virus type 1 (HTLV-1) is a deltaretrovirus that has infected humans for thousands of years. An estimated 10–20 million individuals worldwide are infected with HTLV-1, the majority of whom will remain asymptomatic for life
. For a minority of infected individuals, however, HTLV-1 infection is associated with severe diseases, with 1-5% developing adult T-cell leukemia/lymphoma
 (ALT) and an additional 0.3-4% developing immune-mediated inflammatory disease involving the central nervous system, the eyes, the lungs and/or the skeletal muscles
. Inflammation of the central nervous system (CNS) in HTLV-1-infected subjects results in progressive spasticity and muscle weakness in lower extremities and is termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
. The etiology of HAM/TSP is poorly understood, however it is associated with higher HTLV-1 proviral loads, a higher frequency of HTLV-1-specific CD8+ T-cells and greater production of IFN-γ and TNF-α than that observed in asymptomatic HTLV-1-infected subjects, suggesting the involvement of cellular immune responses in the pathogenesis
[5–8]. As there is no evidence that HTLV-1 infects astrocytes, microglia or neuronal cells, it is unlikely that the damage incurred by these cell populations is mediated by direct recognition of HTLV-1 antigens presented on these cells by HTLV-1-specific CD8+ T-cells. Two potential mechanisms have been proposed to explain how HTLV-1-specific CD8+ T-cells could mediate damage to non-HTLV-1-infected cells. Firstly, this damage could occur simply as a bystander effect of HTLV-1-specific CD8+ T-cells recognizing the HTLV-1-infected T-cells that have been shown to accumulate in the CNS. Secondly, it has been suggested that there may be cross-reactivity of HTLV-1-specific CD8+ T-cells with self antigens expressed in neurons
. Here, we present and explore a third possibility, that HTLV-1-infection may elicit human endogenous retrovirus (HERV) specific CD8+ T-cell responses which, in turn, may be reactive against neurons and other tissues where HERV antigens may be expressed.
Human endogenous retroviruses, the DNA remnants of ancient infectious retroviruses, comprise approximately 8% of the human genome. This complement of HERVs is diverse, with all three major branches of the retroviral tree represented: gamma-epsilon, spuma and delta-lenti-alpha-beta retroviruses
. While the vast majority of HERV insertions do not contain intact open reading frames (ORFs), a recent study has illustrated the potential for even short, disrupted ORFs to serve as a source of immunologically relevant antigens, by mapping the epitope specificity of a renal cell carcinoma reactive CD8+ T-cell to a HERV-E-derived peptide
. As a gross generalization, HERV antigens are not thought to be expressed in healthy tissues, but rather are associated with transformed cell lines and disease states. We have previously presented the hypothesis that HIV-1 infection would result in the induction of HERV expression, either through rescue of HERV function by HIV-1, for example, nuclear export of unspliced HERV RNA by HIV-1 Rev, or through the degradation of host restriction factors which may normally keep HERV expression in check
. Indirect support for this hypothesis is provided by our observation that T-cell responses to peptides derived from diverse HERV families can be detected in HIV-1-infected, but not uninfected, subjects
[12–14]. We have since focused in on the HERV-K(HML-2) lineage of young and relatively intact endogenous retroviruses, and determined that HIV-1 infection results in the induction of Gag and Env protein expression. A HERV-K(HML-2)-Env-specific CD8+ T-cell clone, isolated from an HIV-1-infected subject, specifically responded to and eliminated cells infected with diverse isolates of HIV-1, HIV-2 and SIV
. The establishment of this precedent for induction of HERV expression by an exogenous retroviruses led us to consider whether HTLV-1, as a second human retrovirus, may also drive the expression of HERVs. This idea draws support from a very recent study which demonstrated that the HTLV-1-Tax protein drives transcription from the long-terminal repeats (LTR) of HERV-W8, HERV-H and HERV-K
. In the current study we sought to obtain indirect evidence for the in vivo expression of HERV antigens, by screening PBMC from HTLV-1-infected subjects for T-cell responses to HERV-derived peptides, with a particular focus on the HERV-K(HML-2) lineage.
In addition to providing evidence for the HTLV- 1-induced expression of HERVs, the detection of HERV-specific T-cell responses in HTLV-1-infected subjects would open a line of inquiry into determining whether such responses may contribute to the pathogenesis of HAM/TSP. It is intriguing to note, given the similarities in clinical presentation and pathogenesis of HAM/TSP and multiple sclerosis (MS), that numerous studies have associated HERV polymorphisms or expression levels with MS (reviewed in
). Specifically, HERV-H, HERV-W, and HERV-K have been associated with MS, the same families shown to be induced at the transcriptional level by HTLV- 1-Tax. We posited that HTLV-1 infection would result in the expression of HERV antigens and the induction of HERV-specific T-cell responses, which would, in turn, be reactive against neurons and other tissues which may express low levels of HERV antigens, resulting in the pathologies of HAM/TSP. Consistent with this, we have recently performed a comprehensive screening of human tissues for HERV-K(HML-2)-Gag expression and detected this protein in the central nervous system (neurons, purkinje cells and occasionally ependymal cells), as well as in the endocrine pancreas (few cells in the β-islets of Langerhans) and in the exocrine pancreas (ductal epithelial cells) (Sacha et al. Submitted).