Recent work has shown that tetanus antibody responses are significantly impaired in HIV patients on successful ART (Hart et al. 2007). A recently identified CD4 T-cell subset, known as follicular T cells (TFH) plays a crucial role in the development of humoral immune responses to protein antigens such as tetanus toxoid (King et al. 2008). Follicular CD4 T cells express a chemokine receptor called CXCR5, a protein called inducible co-stimulatory factor (ICOS) and are readily identified in peripheral blood. Follicular CD4 T cells are prone to activation induced cell death which is believed to be a major mechanism of CD4 T-cell depletion in chronic HIV-1 infection and therefore could be a vulnerable target in retroviral disease. A reduction in circulating CD4 TFH numbers and/or function may account for the failure of HIV-1 patients to respond to tetanus vaccination.