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

Abstract

Abstract The level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis. Among host immune factors, the cytokine TNF-α 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-β (LT-β) receptor (LT-βR), also regulates HIV-1 replication. Furthermore, HIV-1 replication is cooperatively stimulated when the distinct LT-βR 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-α and LT-α1β2 act virtually identically to their soluble forms in the regulation of HIV-1 replication. Thus, cosignaling via the LT-β and TNF-α 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-α1β2 is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-α1β2 expression, and HIV-1 replication. Given the critical role that LT-α1β2 plays in lymphoid architecture, we speculate that LT-α1β2 may be involved in HIV-associated abnormalities of the lymphoid organs.