ORIGINAL RESEARCH Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection G Hardy, 1 S Worrell, 2 P Hayes, 1 CM Barnett, 4 D Glass, 4 J Pido-Lopez, 1 N Imami, 1 R Aspinall, 1 J Dutton, 4 B Gazzard, 2 AM Peters 3 and FM Gotch 1 1 Department of Immunology, Imperial College London, Chelsea and Westminster Hospital, London, 2 Department of HIV/ GUM, Chelsea and Westminster Hospital, London, 3 Department of Nuclear Medicine, Addenbrooke’s Hospital, Cambridge, and 4 Department of Imaging, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK Objectives We aimed to provide evidence of thymic reconstitution after highly active antiretroviral therapy (HAART) in HIV-1 infected patients and to correlate this with the restoration of peripheral naı ¨ve T cells. Methods Positron emission tomography (PET) enables definitive evidence of thymic activity, indicating functional potential. In this case study, a single patient who initiatiated HAART demonstrated reconstitution of the naı ¨ve T-cell pool and underwent thymic PET scans at baseline and 2 and 6 months following initiation of therapy. Two patients who failed to demonstrate such reconstitution acted as controls. These patients (mean age 27 years) had chronic HIV infection with low CD4 T-cell counts (mean 82, range 9–160 cells/mL blood). Increased function of the thymus visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells in the periphery measured by flow cytometry, and with numbers of recent thymic emigrants measured by quantification of the numbers of T-cell receptor excision circles (TRECs) in peripheral cells. Results In one patient, clear correlations could be drawn between visible activity within the thymus, as measured by increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naı ¨ve CD4 (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and increased numbers of recent thymic emigrants. A second patient displayed no increase in peripheral CD4 count and no increase in thymic activity. The third patient elected to stop therapy following the 2-month time point. Conclusions The use of PET suggests that thymic activity may increase after HAART, indicating that the thymus has the potential to be functional even in HIV-1 infected persons with low CD4 T-cell counts. Keywords: HAART, HIV, PET, reconstitution, thymus Received: 31 January 2003, accepted 22 September 2003 Introduction The contribution of the thymus to increases in the number of peripheral T cells visualized during highly active antiretroviral therapy (HAART) is a matter of considerable debate. Many hold that, as the thymus normally undergoes early partial involution [1,2], thymic activity is much reduced by early adulthood [3] and is unlikely to contribute to T-cell reconstitution following profound immunosup- pression [4]. Other mechanisms for peripheral T-cell regeneration might be expected to be responsible for the observed increases in the number of CD4 T cells after HAART, such as T-cell redistribution or peripheral expan- sion. Such processes are unlikely to increase an individual’s total T-cell repertoire and provide an inadequate explana- tion of the improved clinical protection against opportu- nistic infections seen during HAART. Active intrathymic T-cell production is likely to be required for the maintenance and reconstitution of the diverse T-cell receptor (TCR) repertoire necessary for long-term immu- nocompetence in individuals whose peripheral T cells Correspondence: Gareth Hardy, Department of Immunology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: 1 44 (0) 20 8746 5974; fax: 1 44 (0) 207 431 0879; e-mail: g.hardy@medsch.ucl.ac.uk r 2004 British HIV Association HIV Medicine (2004), 5, 67–73 67