Following primary human immunodeficiency virus (HIV) infection, HIV disease is characterized by a prolonged period, usually lasting several years, of clinical latency. During this period viremia is generally very low or undetectable, the number of infected cells (i.e. viral burden) in the blood are very low, and the levels of viral replication in these cells are barely detectable. These findings have been interpreted as a reflection of a phase of inactive HIV disease during which time HIV replicates very slowly or its replicating ability is kept under control by effective HIV specific immune responses. However, during this period a general deterioration of immune function and progressive depletion of CD4+ T cells occur; the inevitable outcome is clinically apparent disease. In the present article, we describe a model of disease development in which HIV infection is both active and progressive in the lymphoid organs during the clinically latent period of HIV infection when there are few, if any, signs of disease activity in peripheral blood.