Activation of signal transduction and apoptosis in healthy lymphomonocytesexposed to bystander HIV-1-infected cells

Persistent activation of the immune system is one of the hallmarks of HIV-1 infection. In this study we analysed the induction of factors involved in cytokine signal transduction, such as STAT 1 proteins and IRF-1 mRNA, in no rmal peripheral blood mononuclear cells (PBMC) exposed to HIV-infected cell s, and the induction of apoptosis. Western blot analyses and reverse transc riptase-polymerase chain reaction results indicate that both cells infected with a X4 strain and cells infected with a R5 strain are able to increase intracellular levels of STAT 1 alpha and beta proteins as well as IRF-1 mRN A. This effect was prevented by neutralizing antibodies against interferon- alpha (IFN-alpha). HIV-1-infected cells dose-dependently induced apoptotic commitment in normal PBMC, as revealed by DNA fragmentation analysis, but t his was not accompanied by an increase of caspase-3 activity, even if a sli ght up-regulation of IL-1 beta -converting enzyme mRNA was detected. Apopto sis induction could be abrogated mainly by antibodies against tumour necros is factor-alpha (TNF-alpha) and, to a lesser extent, by antibodies against IFN-gamma. All these findings suggest that uninfected PBMC can undergo acti vation of signal transduction and apoptosis after exposure to bystander HIV -infected cells, subsequent to the induction of cytokines such as IFNs and TNF-alpha.