Thorough research on HIV is progressively enabling us to understand the intricate mechanisms that link HIV‐1 infection to the onset of immunodeficiency. The infection and depletion of CD4⁺ T cells represent the most fundamental events in HIV‐1 infection. However, in recent years, the role played by chronic immune activation and inflammation in HIV pathogenesis has become increasingly apparent: quite paradoxically, immune activation levels are directly associated with HIV‐1 disease progression. In addition, HIV‐1‐infected patients present intriguing similarities with individuals of old age: their immune systems are characterized by a loss of regenerative capacity and an accumulation of ageing T cells. In this review, we discuss the potential reasons for the establishment of sustained immune activation and inflammation from the early stages of HIV‐1 infection, as well as the long‐term consequences of this process on the host immune system and health. A simplified model of HIV pathogenesis is proposed, which links together the three major facets of HIV‐1 infection: the massive depletion of CD4⁺ T cells, the paradoxical immune activation and the exhaustion of regenerative capacity. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.