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Signaling Through the Lymphotoxin-ß Receptor Stimulates HIV-1 Replication Alone and in Cooperation with Soluble or Membrane-Bound TNF-¹

William L. Marshall, Brigitta M. N. Brinkman^*, Christine M. Ambrose, Patricia A. Pesavento^*, Adele M. Uglialoro^*, Edna Teng, Robert W. Finberg, Jeffrey L. Browning and Anne E. Goldfeld^2,

^* Center for Blood Research and Division of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and Biogen, Inc., Cambridge, MA 02138

The level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis. Among host immune factors, the cytokine TNF- has previously been shown to increase HIV-1 replication in various monocyte and T cell model systems. Here, we demonstrate that signaling through the TNF receptor family member, the lymphotoxin-ß (LT-ß) receptor (LT-ßR), also regulates HIV-1 replication. Furthermore, HIV-1 replication is cooperatively stimulated when the distinct LT-ßR and TNF receptor systems are simultaneously engaged by their specific ligands. Moreover, in a physiological coculture cellular assay system, we show that membrane-bound TNF- and LT-₁ß₂ act virtually identically to their soluble forms in the regulation of HIV-1 replication. Thus, cosignaling via the LT-ß and TNF- receptors is probably involved in the modulation of HIV-1 replication and the subsequent determination of HIV-1 viral burden in monocytes. Intriguingly, surface expression of LT-₁ß₂ is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-₁ß₂ expression, and HIV-1 replication. Given the critical role that LT-₁ß₂ plays in lymphoid architecture, we speculate that LT-₁ß₂ may be involved in HIV-associated abnormalities of the lymphoid organs.

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