Interferons (IFN) are antiviral proteins that may be important in mediating cellular defenses against Epstein‐Barr virus (EBV) infection. However, the means by which IFN‐α, ‐β and ‐γ modify EBV infectivity are not clear. We have evaluated the effects of purified recombinant preparations of all three classes of IFN on EBV‐induced B lymphocyte proliferation and Ig secretion. When added early after EBV infection, all three recombinant IFN reduced B cell outgrowth and Ig secretion. IFN‐γ exerted a 7‐10‐fold more potent antiviral effect than IFN‐α or ‐β. All three types of IFN act directly on B cells. Monocytes and natural killer cells are not necessary for the anti‐EBV activity. Of the three recombinant IFN, only IFN‐γ reduced EBV‐induced proliferation and Ig secretion when added 3–4 days after virus infection; IFN‐α/β were only effective up to 24 h. B lymphoblastoid lines already transformed by EBV are insensitive to the anti‐proliferative actions of all three types of IFN.

On the basis of these findings, we propose three phases of regulation during EBV infection. In the early phase, EBV‐infected cells can be regulated by all IFN. Subsequently, there is an intermediate period where only IFN‐γ is capable of directly affecting EBV‐induced B cell responses. In the third phase, B lymphocytes become insensitive to direct actions of all IFN and are now subject to regulation only by cytotoxic cells.