The Human Papillomavirus E7 Oncoprotein Abrogates Signaling Mediated by Interferon-alpha

Greater than 95% of all cervical carcinomas have been found to be associated with "high-risk" human papillomavirus (mainly types 16 and 18) infections, with the viral E6 and E7 oncoproteins essential for neoplastic development and maintenance. Interferon-alpha (IFNalpha) is used in the treatment of HPV infections yet both in vivo and in vitro data suggest that the virus has developed mechanisms to avoid the effects of interferon. Here we show that the HPV16 E7 oncoprotein is able to inhibit the induction of IFNalpha-inducible genes but has no effect of IFNgamma-inducible genes. Expression of E7 correlates with the loss of formation of the interferon-stimulated gene factor 3 (ISGF3) transcription complex. Moreover, in the presence of E7, p48, the DNA-binding component of ISGF3, was unable to translocate to the nucleus upon IFNalpha stimulation. A direct protein-protein interaction was identified between E7 and p48 with the site of interaction within E7 defined as the region between amino acids 17-37, a domain that includes the binding site for the retinoblastoma protein, pRb. These results suggest that HPV, via E7, targets p48, resulting in the loss of IFNalpha-mediated signal transduction and may provide a means by which HPV can avoid the innate immune system.