Tumour-associated viruses produce antigens that, on the face of it, are ideal targets for immunotherapy. Unfortunately, these viruses are experts at avoiding or subverting the host immune response. Cervical-cancer-associated human papillomavirus (HPV) has a battery of immune-evasion mechanisms at its disposal that could confound attempts at HPV-directed immunotherapy. Other virally associated human cancers might prove similarly refractive to immuno-intervention unless we learn how to circumvent their strategies for immune evasion.

We have identified a major T-cell epitope, amino acids [48][49][50][51][52][53][54] in the E7 open reading frame protein of human papillomavirus (HPV) type 16. Lymph node cells from mice immunized with synthetic peptides containing DRAHYNI proliferated and produced interleukin when challenged in vitro with peptide or whole HPV-16 E7 fusion protein. The T epitope was recognized in association with all five major histocompatibility complex class II I-A and I-E alleles tested. Synthetic peptides consisting of DRAHYNI linked to major B-cell epitopes on the E7 molecule formed immunogens capable of eliciting strong antibody responses to HPV-16 E7. The T epitope could provide help for the production of antibody to several B epitopes simultaneously, including a B epitope of HPV-18 E7 protein. Mice immunized with a peptide containing DRAHYNI and B epitope and, at a later date, infected with recombinant vaccinia E7 virus, displayed secondary antibody responses to E7. Because E7 has a role in cell transformation and is the most abundant viral protein in HPV-associated neoplastic cervical epithelial cells, the data have implications for vaccine strategies.Circumstantial evidence implicates host immune mechanisms in the control of human papillomavirus (HPV)-associated tumors of the anogenital epithelium (1), and there is an increased risk of squamous cell carcinoma of the cervix and vulva but not of control organs, such as breast and rectum, in immunosuppressed allograft recipients (2). E7 is the most abundant viral protein in HPV-16-containing CaSki and SiHa squamous carcinoma cell lines and in HPV-18-containing HeLa and C4-1 lines (3). DNA-transfection experiments implicate the E7 open reading frame protein in in vitro transformation of mouse fibroblasts (4), rat epithelial cells (5), and primary human keratinocytes (6). Cooperation with an active ras oncogene leads to full transformation (5), and there is a requirement for continued expression of the E7 gene to maintain the transformed phenotype (7). The E7 protein may be immunogenic after infection with HPV, as anti-E7 antibodies have been described in the serum of "20% of patients with HPV-16-associated cervical lesions (8, 9).These observations suggest that the E7 protein merits consideration as a candidate antigen for a potential vaccine against HPV infection. We have recently described the major immunodominant B epitopes in HPV-16 E7 (10) and HPV-18 E7 (11) defined by monoclonal antibodies. In this study we have defined, using synthetic peptides, a major T helper (Th) epitope in HPV-16 E7. MATERIALS AND METHODSSynthetic Peptides. Peptides were synthesized by using derivatized N-tert-butoxycarbonyl (t-Boc) amino acids on benzhydryl resin (12) or using 9-fluorenylmethoxycarbonyl (Fmoc) chemistry on an Applied Biosystems 431A peptide synthesizer. The amino acid composition, toxicity, and mitogenicity of all peptides were checked. Peptides 8Q and GF15 were amino acid sequenced.HPV-16 E7 Protein. HPV-16 E7 protein was produced as MS2 fusion protein from a heat-ind...

The co-evolution of papillomaviruses (PV) and their mammalian hosts has produced mechanisms by which PV might avoid specific and non-specific host immune responses. Low level expression of PV proteins in infected basal epithelial cells, together with an absence of inflammation and of virus-induced cell lysis, restricts the opportunity for effective PV protein presentation to immunocytes by dendritic cells. Additionally, PV early proteins, by a range of mechanisms, may restrict the efficacy of antigen presentation by these cells. Should an immune response be induced to PV antigens, resting keratinocytes (KC) appear resistant to interferon-gamma-enhanced mechanisms of cytotoxic T-lymphocyte (CTL)-mediated lysis, and expression of PV antigens by resting KC can tolerise PV-specific CTL. Thus, KC, in the absence of inflammation, may represent an immunologically privileged site for PV infection. Together, these mechanisms play a part in allowing persistence of PV-induced proliferative skin lesions for months to years, even in immunocompetent hosts.

No abstract