To investigate the dynamic interplay between human immunodeficiency virus type I (HIV-1) replication and the extent of immune destruction in HIV-1-infected children, virus burden in lymphoid tissues (LN) and peripheral blood was compared with changes in LN architecture and cytokine levels constitutively expressed in LN. In agreement with results of a preliminary study, the plasma HIV-1 RNA level correlated with the amount of provirus in LN. However, the level was also associated with a degree of destruction of lymphoid follicular architecture and an alteration of immune cytokine expression. Expression of interleukin (IL)-4 was higher in LN with higher virus replication. Reduction of plasma viremia was associated with an increase in IL-2 mRNA levels in LN. These findings suggest that measurable virus burden in the peripheral blood is not a simple reflection of viral replication in LN but is also influenced by the extent of progressive immune destruction.