Signaling through the lymphotoxin-beta receptor stimulates HIV-1 replication alone and in cooperation with soluble or membrane-bound TNF-alpha

The level of ongoing HIV-1 replication within an individual is critical to HIV-1 pathogenesis. Among host immune factors, the cytokine TNF-cu has prev iously been shown to increase HIV-1 replication in various monocyte and T c ell model systems. Here, we demonstrate that signaling through the TNF rece ptor family member, the lymphotoxin-beta (LT-beta) receptor (LT-beta R), al so regulates HIV-1 replication. Furthermore, HIV-1 replication is cooperati vely stimulated when the distinct LT-beta R and TNF receptor systems are si multaneously engaged by their specific ligands, Moreover, in a physiologica l coculture cellular assay system, we show that membrane-bound TNF-alpha an d LT-alpha(1)beta(2) act virtually identically to their soluble forms in th e regulation of HIV-1 replication. Thus, cosignaling via the LT-beta and TN F-alpha receptors is probably involved in the modulation of HIV-1 replicati on and the subsequent determination of HIV-1 viral burden in monocytes, Int riguingly, surface expression of LT-alpha(1)beta(2) is up-regulated on a T cell line acutely infected with HIV-1, suggesting a positive feedback loop between HIV-1 infection, LT-alpha(1)beta(2) expression, and HIV-1 replicati on. Given the critical role that LT-alpha(1)beta(2) plays in lymphoid archi tecture, we speculate that LT-alpha(1)beta(2) may be involved in HIV-associ ated abnormalities of the lymphoid organs.