[Frontiers in Bioscience 14, 2889-2903, January 1, 2009]

The immune control of HTLV-1 infection: selection forces and dynamics

Charles R M Bangham1, Kiran Meekings1, Frederic Toulza1, Mohamed Nejmeddine1, Endre Majorovits3, Becca Asquith1, Graham P Taylor2

1Department of Immunology, Imperial College, Norfolk Place, London W2 1PG, UK, 2 Department of GU Medicine and Communicable Diseases, Imperial College, Norfolk Place, London W2 1PG, UK, 3 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

TABLE OF CONTENTS

1. Abstract
2. Risk of HAM/TSP depends on HTLV-1 proviral load
3. HTLV-1 proviral load is correlated with the HTLV-1-specific CTL activity
4. HTLV-1 infection accelerates the turnover of both CD4+ and CD8+ T cells in vivo
5. Persistent expression of HTLV-1 in vivo: T-cell proliferation and directional, triggered cell-cell spread of enveloped HTLV-1 virions across the virological synapse
6. The rate of HTLV-1 proviral expression varies among hosts and among T-cell clones within one host
7. The genomic integration site of HTLV-1 determines the rate of HTLV-1 proviral expression and the risk of HAM/TSP
8. Host genotype determines the efficiency of the immune control of HTLV-1 and the outcome of HTLV-1 infection
9. CTL frequency is not a useful guide to CTL efficacy 10. FoxP3+ CD4+ "Treg" frequency is negatively correlated with CTL lysis rate 11. Conclusion: selection and persistence of HTLV-1-infected T cells in vivo 12. Acknowledgements 13. References

1. ABSTRACT

Cytotoxic T lymphocytes (CTLs) play a central role in the protective immune response to human T-lymphotropic virus 1 (HTLV-1). Here we consider two questions. First, what determines the strength of an individual's HTLV-1-specific CTL response? Second, what controls the rate of expression of HTLV-1 in vivo, which is greater in patients with HAM/TSP than in asymptomatic carriers with the same proviral load? Recent evidence shows that FoxP3+CD4+ T cells are abnormally frequent in HTLV-1 infection, and the frequency of these cells is inversely correlated with the rate of CTL lysis of HTLV-1-infected cells, suggesting that FoxP3+CD4+ cell frequency is an important determinant of the outcome of HTLV-1 infection. There is also new evidence that the rate of expression of HTLV-1 in vivo is associated with the transcriptional activity of the flanking host genome. We suggest that the frequencies of HTLV-1-infected T cell clones in vivo are determined by a dynamic balance between positive and negative selection forces that differ among the clones