Using ex vivo antigen-specific T-cell analysis, we found that symptomatic cytomegalovirus recrudescence in transplant recipients was coincident with reduced expression of gamma interferon (IFN-␥) by virus-specific CD8؉ T cells and an up-regulation of CD38 expression on these T cells, although there was no significant change in the absolute number of virus-specific cells (as assessed by major histocompatibility complex-peptide multimers). In contrast, HLA class I-matched transplant patients with asymptomatic viral recrudescence showed increased expansion of antigen-specific T cells and highly stable IFN-␥ expression by epitope-specific T cells. These studies suggest that a strong functional T-cell response plays a crucial role in defining the clinical outcome of acute viral recrudescence.The clinical presentation of acute latent viral infections and its interaction with host T-cell responses have recently been investigated in order to understand the dynamics of immune regulation and to develop better therapeutic strategies (5,9,10,20). Previous studies have proposed a role for a number of potential factors, such as viral load and cytokine dysregulation, in controlling the symptoms of acute viral infection (1, 17). It is entirely feasible that the dynamics of emergence of the virus-specific T-cell response during the early stages of viral recrudescence may delimitate the patterns of clinical symptoms in different individuals (11,13,16). Indeed, massive expansion of CD8 ϩ T cells specific for Epstein-Barr virus latent and lytic antigens, which is often a feature of acute EpsteinBarr virus infection, suggests that these T-cell responses are recruited to control the active viral infection (2). However, understanding the biological significance and the longitudinal dynamics of these T cells during acute viral infections in humans is often difficult and is complicated by the nature of immune responses in naturally outbred individual patients. We have addressed some of these limitations by analyzing the dynamics of T-cell responses to a panel of CD8 ϩ T-cell epitopes in a group of HLA class I-matched unrelated human subjects undergoing acute human cytomegalovirus (HCMV) infection with contrasting clinical symptoms. We studied three

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