Localization of Pepstatinʹs Inhibitory Action during Fc-Mediated Antibody Internalization: Possible Implications for Antibody-Mediated Viral Transmission

Antibody internalization via Fc receptors is an important cellular mechanism, possibly facilitating the entry of antigenic peptides or viral particles into cells when specific antibodies are present at the periphery. Using an experimental model of trophoblast cells, we have shown that anti-p21ras monoclonal antibodies can use IFN-γ-induced surface Fcγ receptors to enter the cell. This entry of anti-p21ras antibodies ultimately inhibits IFN-γ-mediated class II antigen induction. Since there may be obvious and inevitable harmful aspects of this mechanism, during which Fc-mediated viral particle or autoantigen transport may occur, we concentrated efforts on defining a potent inhibitor able to eliminate such uptake. The results presented here show that the protease inhibitor pepstatin A efficiently inhibits Fcγ receptor induction by IFN-γ and also blocks the endocytic pathway followed by an antibody when it enters the cell at the level of early endosomal compartments. We thus postulate that the use of pepstatin A, because of its inhibition of autoantigen presentation or viral transmission, including that of HIV, may find important applications in therapeutic protocols.