Germinal centers play an important role in the pathogenesis of HIV-1-induced lymphadenopathy. Cell-free retrovirus particles, gag proteins of HIV-1, and cells expressing viral RNA can be detected in these areas of the lymph node. In the present study, the ultrastructural changes and the interactions of virus with different cell types of the germinal centers were investigated. We compared the alterations of lymph nodes obtained shortly after seroconversion with those seen in longstanding lymphadenopathy. The results demonstrated that germinal centers were already infected in the early phase of the disease. However, the number of cell free virions was low. During the course of the disease, large amounts of cell free virions accumulated in the germinal centers. The persistence of germinal center infection for up to 2 years was demonstrated by detecting retrovirus particles in repeated biopsy specimens. In addition, the presence of numerous small, moderately electron dense structures that might represent defective particles of HIV-1 and influence the course of the disease were described. HIV-1 was found to replicate in lymphocytes, macrophages, and follicular dendritic cells. Quite possibly, a genomic shift may occur at the time of transmission of the virus to a novel target cell, thus, germinal centers may be one of the anatomic sites where HIV-1 acquires the ability to develop into a variant with preferential tropism for a given cell type.