ORIGINAL RESEARCH Molecular correlates in AIDS patients following antiretroviral therapy: diversi®ed T-cell receptor repertoires and in vivo control of cytomegalovirus replication S Worrell, 1,2 J Deayton, 3 P Hayes, 1 VC Emery, 3 F Gotch, 1 B Gazzard 2 and E-L Larsson-Sciard 1 1 Department of Immunology and 2 The Kobler Centre, Chelsea and Westminster Hospital, and 3 Royal Free Hospital and University College Medical School, London, UK Objectives To evaluate whether successful, long-term immune reconstitution in vivo can be achieved in end-stage AIDS patients following antiretroviral therapy (ART). Methods A 1-year prospective study of changes of CD4+ and CD8+ T-cell surface phenotypes, T-cell receptor (TCR) repertoires and capacity to control in vivo replication of cytomegalovirus (CMV) was performed in ®ve treatment-naive end-stage AIDS patients (median CD4+ T-cell counts of 19 cells/mL) following therapy. Proportions of CD45RA+, CD45RO+ and CD28+ cells within the CD4+ and CD8+ subsets, were determined by ¯ow cytometry. Changes in TCR Vb repertoires within the CD4+ and CD8+ T-cell compartments were evaluated using CDR3 spectratyping. CMV replication was determined by a sensitive polymerase chain reaction (PCR) assay using whole blood. Results Following ART, proportionate increases in `naive' (CD45RA+) and `memory' (CD45RO+) T cells were observed within both CD4+ and CD8+ T-cell subsets, while increased numbers of CD28+ T cells were mainly observed within the CD4+ subset. Diversi®cation of CD4+ and CD8+ TCR repertoires was established concomitantly with renewed in vivo control of CMV replication. Conclusions An important degree of molecular and functional immune recovery is possible in end-stage AIDS patients introduced to therapy. Diversi®cation of TCR repertoires and the in vivo restoration of immunocompetence to control opportunistic infections clearly show that an important degree of molecular immune reconstitution is established following the initiation of ART even in late-stage AIDS. Key words: AIDS, CDR3 spectratyping, cytomegalovirus, protease inhibitors Received: 17 April 2000, accepted 17 August 2000 Introduction The severe immunosuppression that characterizes end- stage AIDS is in part the result of an impairment of T-cell responsiveness and highly skewed T-cell repertoires. Although antiretroviral therapy (ART) is known to decrease the incidence of opportunistic infections in chronically infected individuals, it remains unclear whether this is because of expansion of existing T cells or a result of emergence of new stem cell-derived T cells. A biphasic increase in CD4+ T-cell counts, initially involving memory (CD45RO+) followed by a slow increase in naive (CD45RA+) CD4+ T cells, has been described in ART-treated patients with chronic HIV disease and has been suggested to re¯ect an initial redistribution of cells previously trapped in lymphoid tissue followed by a low- level production of new T cells [1,2]. Others have reported that the CD4+ T-cell pool is mainly regenerated by Correspondence: Dr Eva-Lotta Larsson-Sciard, Department of Immunology, ICSM, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK; e-mail: e.larsson-sciard@ic.ac.uk 11 Ó 2001 British HIV Association HIV Medicine (2001) 2, 11±19 Ó 2001 British HIV Association HIV Medicine (2001) 2, 11±19