Role of CD40 ligand dysregulation in HIV-associated dysfunction of antigen-presenting cells

Cellular interactions between antigen-presenting cells and activated CD4+ T cells are central to the regulation of adaptive immunity. Among the many receptor-ligand pairs involved, the critical importance of CD40-CD40 Ligand (CD40L) interactions has been demonstrated in many experimental systems. Dysregulation of antigen-presenting cell function is a hallmark of HIV-associated defects in cell-mediated immunity. Much evidence suggests a mechanistic role for defective CD40-CD40L interactions in such a defect. Consistent with this hypothesis, the capacity to upregulate CD40L on purified CD4+ T cells becomes progressively impaired in HIV infection, in parallel with the progression of clinical immunosuppression. The mechanisms underlying CD40L dysregulation in HIV infection remain unknown. Because CD40L expression is tightly regulated (transcriptionally, post-transcriptionally and post-translationally), HIV may interfere at several levels. However, a transcriptional defect in CD40L expression, mediated by the engagement of CD4 by HIV gp120, appears to play a primary role. Clear elucidation of mechanism may well lead to the development of novel immunotherapeutic approaches to HIV infection.