The influence of HLA and the cell mediated immune response to HPV-16 E7 on cervical disease regression, viral clearance, and vaccine efficacy
Kines, Rhonda Christine
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A productive and successful cellular immune response is crucial in controlling and preventing both the onset and recurrence of infectious disease. When the immune system fails to clear human papillomavirus (HPV), a persistent infection develops that can result in malignancy. In our studies we sought to examine both the influence of the naturally occurring immune response to HPV-16 E7 as well as a role for HLA alleles in controlling cervical disease and HPV infection. Key findings from our study were: (1) immunological responders infected with HPV-16 were incapable of clearing their viral infection as efficiently and as rapidly compared to immunological non-responders, (2) HLA-A*02, -A*24, -A*33, -B*08, -B*15, and -B*58 alleles provide protective effects from incidence of abnormal cytology and may facilitate more rapid disease regression or viral clearance, and (3) we did not detect any HLA alleles conferring susceptibility. In a separate study, we examined a role for HLA molecules in modulating the immune response using an E7 DNA vaccine strategy. Utilizing HLA-DRB1*04 and HLA-DRB1*03 transgenic mice, representing susceptible and protective HLA-DRB1 alleles respectively, we examined the immunological responses elicited after vaccination with a DNA vaccine targeting E7 into the class II processing and presentation pathway (Sig/E7/LAMP-1). Immunization with this construct resulted in both, enhanced proliferation of T cells from HLA-DRB1*04 mice and increased secretion of the Th2 cytokine, IL-5, from T cells from HLA-DRB1*03 mice, upon in vitro stimulation with E7. Furthermore, when challenged with recombinant vaccinia virus expressing E7, HLA-DRB1*03 and HLA-DRB1*04 mice immunized with E7 DNA elicited an immune response capable of controlling challenge with vaccinia virus expressing E7. However HLA-DRB1*03 mice immunized with Sig/E7/LAMP-1 DNA were not able to control this challenge. HLA-DRB1*04 mice immunized with Sig/E7/LAMP-1 DNA exhibited some level of protection, although this did not reach statistical significance. Our results suggest that fusing E7 to LAMP-1 resulted in a less beneficial immunological response and this construct should be examined carefully prior to implementation in humans. Taken collectively, our results highlight the importance of understanding the influence of HLA type and the anti-viral cell mediated immunological response in women who have successfully cleared their infections and regressed to normal cytology.