Stimulation of bystander T-cell proliferation by tumor necrosis factor produced by HIV-1-infected macrophages.

Abstract

Objective: Cocultivation of the CD4+CD95+ T-cell line (MT4) with monocyte-derived macrophages (MDMs) infected with the HIV-1 resulted in costimulation of proliferation and apoptosis after 20 hours of contact. This study sought to determine whether tumor necrosis factor (TNF) produced by HIV-1-infected MDMs was involved in the costimulation of cell proliferation, the apoptotic pathway, or both.

Study design/methods: MT4 cells were cocultivated with infected or noninfected MDMs in the presence or absence of soluble TNF receptors (sTNFRs) or antagonistic anti-Fas antibody (ZB4). Cell proliferation was assessed by measuring thymidine incorporation. Apoptosis was monitored by using flow cytometry and enzyme-linked immunosorbent assay (ELISA).

Results: Thymidine incorporation was higher in cells cocultivated with HIV-infected or noninfected MDMs than it was in controls grown in culture medium. It also was higher in cells cocultivated with HIV-infected MDMs than it was in cells cocultivated with noninfected MDMs. sTNFRs blocked the increase of thymidine incorporation specifically induced by HIV-infected MDMs. They did not inhibit apoptosis at 20 hours. Cells recovered from cocultures involving HIV-infected or noninfected MDMs exhibited decreased sensitivity to apoptosis induced through the Fas receptor.

Conclusion: TNF produced by HIV-infected MDMs acts as an accessory T-cell growth factor that synergizes with an as yet unidentified growth-inducing signal or signals produced by HIV-infected and noninfected MDMs. Stimulation of cell proliferation by MDMs induces transient resistance to Fas-induced apoptosis.