The cellular immune response to infection with the human leukaemia virus HTLV-1

The HTLV-1 endemic region of Japan

The human T-lymphotropic virus type 1 (HTLV-1) causes two distinct types of disease: the aggressive T-cell leukaemia/lymphoma and a number of chronic inflammatory conditions, notably HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).  In 95% of HTLV-1-infected individuals the virus persists indefinitely without causing disease.  Neither the pathogenesis of these diseases nor the mechanism of persistent infection of HTLV-1 has been well understood.

Key experimental discoveries and contributions

• Host genotype determines the outcome of HTLV-1 infection.

HLA class 1 genes HLA-A*-2 and HLA-Cw*08 protect against HTLV-1-associated neurological disease in southern Japan (8,18, 19, 30).

• Cell-mediated immune response protects against HTLV-1

Cytotoxic T lymphocytes (CTLs) suppress spontaneous HTLV-1 expression in autologous ex vivo naturally infected lymphocytes (3,15)

A strong CTL response is associated with a lower proviral load and exerts selection on the virus in vivo (24, 25)

• T-cell fratricide is induced by HTLV-1

 HTLV-1 infects CD8+ T cells (CTLs) which are then killed by their 'brother' CTLs (16).

• The helper T cell response to HTLV-1 is exaggerated in patients with HAM/TSP

First description of the CD4+ T cell response to HTLV-1.  The results suggest that CD4+ T cells contribute to inflammatory tissue damage in HAM/TSP (12-14).

• Virological synapse

HTLV-1 spreads directly between lymphocytes when an infected cell contacts another cell (17).  This was the first description of a virological synapse.  The molecular triggers have also been identified (10, 22).

•  T cell turnover in vivo is accelerated by HTLV-1 infection

Metabolic labelling of lymphocytes in human volunteers revealed abnormally rapid proliferation of HTLV-1-expressing lymphocytes and CD8+ T-cells in vivo (5).

• Dynamics of the immune response to persistent viral infection: mathematical analysis of experimental data

Because of the complexity of the dynamics in the continuous battle between a persistently replicating virus and the immune system, mathematical analysis of experimental data is essential in order to ensure  logical rigour and consistency in the interpretation of experimental results.  Key publications include (1, 2, 4, 26, 31).

Reviews of the work of the group are found at (6, 7).