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HIV infection is a disease primarily of lymphatic tissues, in which most viral replication occurs in CD4 T cells. The most common measures of the impact of HIV infection are made by counting CD4 T cells in peripheral blood. Peripheral blood, however, contains only 2% of the total CD4 cell population in the body and these are typically effector memory cells in transit; the vast majority of CD4 cells reside in the secondary lymphoid tissues (e.g. lymph nodes and mucosal lymphatic tissues) and the impact of HIV replication is most profound on the population residing within these compartments. Within organized follicular aggregates in mucosal tissues and the very precise structures of lymph nodes most viral replication occurs in the parafollicular T-cell zone, both in primary infection and throughout the course of the disease, such that by the time the patient presents with symptoms of HIV seroconversion approximately 50% of the population is already depleted. Therefore, if we are to understand the pathophysiology and pathogenesis of HIV and its related complications fully, we need to examine the structure and function of secondary lymphoid tissues before and during HIV infection and before and during HIV treatment. This may provide valuable insights into the underlying pathogenesis of a range of disorders associated with HIV infection, and potentially aid in the development of therapies aimed at emerging complications of long-term HIV infection.