The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/1/81/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 1, January 6, 1997 81-90

Articles

Membrane Tumor Necrosis Factor (TNF) Induced Cooperative Signaling of TNFR60 and TNFR80 Favors Induction of Cell Death Rather Than Virus Production in HIV-infected T Cells

Janis K. Lazdins*, Matthias Grell{ddagger}, Maja R. Walker*, Kathie Woods-Cook*, Peter Scheurich{ddagger}, and Klaus Pfizenmaier{ddagger}

From the * Division Pharma, Ciba, 4002 Basel, Switzerland; and {ddagger} Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany

Tumor necrosis factor (TNF) and lymphotoxin (LT) are highly pleiotropic cytokines that play a central role in regulating HIV-1 replication. These cytokines express their activities through two membrane receptors, TNFR60 (p55-60) and TNFR80 (p75-80). In the present study we have demonstrated by means of antagonistic and agonistic receptor-specific antibodies that in latently infected lymphocytic (ACH-2) cells the TNFR60 plays a dominant role in signaling HIV production, although selective activation of TNFR80 by receptor-specific antibodies can also induce HIV production. Unexpectedly, when both TNFRs were activated simultaneously by agonistic antibodies or coculture with cells expressing a noncleavable membrane form of TNF, HIV production was downregulated and induction of cell death was enhanced in ACH-2 cells. More relevant, in vitro HIV-infected peripheral blood lymphocytes cocultured with cells expressing membrane TNF underwent rapid induction of apoptosis with a subsequent reduced HIV production of these lymphocytes cultures. This was not observed with HIV-infected lymphocytes treated with soluble TNF. These data provide evidence for the differential trigger potential of membrane versus soluble TNF and show that TNFR80 is an important modulator of TNF responsiveness of HIV-infected T cells via cooperative signaling with TNFR60.

Address correspondence to Klaus Pfizenmaier, Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.

1 Abbreviations used in this paper: FDA, fluorescein diacetate; LT, lymphotoxin; RT, reverse transcriptase.


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