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Klara Tenner-Racz, Hans-Jürgen Stellbrink, Jan van Lunzen, Claus Schneider^||, Jan-Peter Jacobs^*, Birgit Raschdorff^*, Gudrun Großschupff^*, Ralph M. Steinman^¶, and Paul Racz^*

From the ^* Department of Pathology and Körber Laboratory for AIDS Research, Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany; the Medical Department, Eppendorf University, 20251 Hamburg, Germany; the Department of Surgery, Eppendorf University, 20251 Hamburg, Germany; the ^|| Carl Zeiss Company, 20537 Hamburg, Germany; and the ^¶ Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York 10021

The efficacy of triple drug therapy for HIV-1 infection encourages its early use to prevent damage to the immune system. We monitored the effects of such therapy on 12 patients with 14–75-mo histories of minimal disease, i.e., CD4⁺ counts constantly >500/µl and little or no lymph node enlargement. In this way, we could first determine the extent of viral replication and immunoarchitectural changes in unenlarged nodes early in disease, and second follow the response to triple therapy in plasma and lymphoid tissue in tandem. As is known for lymph nodes with more advanced disease, the germinal centers showed productively infected T cells, i.e., CD4⁺CD1a^–CD68^– cells labeling intensely for HIV-1 RNA after in situ hybridization. The unenlarged nodes also showed extensive HIV-1 RNA retention on a well-preserved, follicular dendritic cell (FDC) network, and the follicles were abnormal. There were numerous CD8⁺ cells, many expressing TIA-1 granule antigen. Also, in contrast to normal follicles, CD4⁺ T cell proliferation was active, with marked increases in the number of cycling, Ki-67⁺CD4⁺CD45R0⁺ cells. After 28 d and 3 mo of therapy, productively infected T cells decreased dramatically and often were not apparent. The labeling of the FDC network for viral RNA also decreased, but not for gag protein. We conclude that HIV-1 replicates and accumulates in lymphoid organs before damage of the immune system, that at this stage of disease de novo production of T cells occurs in the lymphoid tissue, and that the infection is sensitive to triple drug therapy in both plasma and lymph nodes.

Abbreviations used: APAAP, alkaline phosphatase anti–alkaline phosphatase; ELT, extrafollicular lymphoid tissue; FDC, follicular dendritic cell; GC, germinal center; PGL, persistent generalized lymphadenopathy; SSC, standard saline citrate.

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