Human immunodeficiency virus (HIV-1) infection is characterized by an inexorable decline in CD4 + T cells. CD4+ T cells have been shown play an important role in maintaining memory cytotoxic T cell (CTL) responses in a number of viral infections. Recently, in mouse models, it has been demonstrated that CD4 + T cells help CTL responses via CD40 ligand-CD40 interactions. This project examined the role of CD4+ T cells and CD40 ligand in producing an effective memory cytotoxic T cell (CTL) response in both normal human volunteers and HIV-1 infected individuals. CD4 help was required for optimal in-vitro CTL responses against influenza in normal subjects. CD40 ligand enhanced CTL responses and was able to completely substitute for CD4 help in these normal subjects in vitro. In HIV-1 infected individuals, CD4 help was required for optimal HIV-1-specifc in-vitro CTL responses in 9/10 patients. In one long term non-progressor patient, optimal CTL responses could be induced in-vitro without CD4 help. CD40 ligand could enhance CTL responses in most HIV-1 infected patients; however, CD40 ligand could not completely replace CD4 help in some patients. The mechanism of poor responsiveness to CD40 ligand was shown to involve dysfunction of circulating CD8+ memory T cells, which could be corrected by addition of cytokines such as interleukin-2. In addition, interleukin-15 produced by CD40LT-stimulated dendritic cells may be an additional mediator of CD40LT-induced expansion of memory CTL responses. Our findings demonstrate the importance of CD4 help and CD40 ligand in inducing effective memory anti-viral CTL responses, and suggest that some HIV-infected patients have an intrinsic defect of CD8+ T cells.
