Noncytotoxic CD8+ T cells may play a critical role in preventing progression to disease following human immunodeficiency virus (HIV) infection. This antiviral response, mediated by a novel CD8+ T-cell antiviral factor (CAF), occurs soon after infection and is maintained in asymptomatic individuals. Here, Jay Levy and colleagues propose that this antiviral activity represents a natural cellular immune reaction that controls HIV production and protects the host from potential harmful effects of cytotoxic T lymphocytes.