The high-level proliferative responses observed in our study might reflect the fact that BP is an intra-epithelial vulvar and perineal cutaneous and mucosal disease that progresses exceptionally to invasive carcinoma. Indeed,

the evolution of BP towards invasive carcinoma is present in fewer Selleckchem Hydroxychloroquine than 3–4% of patients [2,3], whereas CIN3 evolves towards invasion in about 15% of cases [6]. Among 18 large peptides of the proteins E6 and E7, two were recognized in proliferative assays as immunodominant by T cells from 10 of 16 women (62%) at entry into the present study, namely E6/2 (aa 14–34) and E6/4 (aa 45–68). Four other peptides, E6/7 (aa 91–110), E7/2 (aa 7–27), E7/3 (aa 21–40) and E7/7 (aa 65–87), were recognized by only 12% of the women in proliferative or ELISPOT–IFN-γ tests. The E6 and E7 protein regions implicated in T cell recognition during HPV infection have not yet been well defined because Copanlisib cost of the usually low frequency of anti-HPV blood T cell responses and of the difficulties in studying them. In protein E6, some peptides, including or overlapping our peptides E6/2 (aa 14–34) and E6/4 (aa 45–68), have already been described as recognized preferentially by CD4+ T cells. Among them, peptide E6 42–57, that is restricted by the HLA-DR7

molecule, has already been identified [34]. Regions E6 1–31, 22–51 and 24–45 can be also immunogenic for CD4+ T cells, as shown in CIN or sexually active healthy women [35]. Region E6 42–71, which includes peptide E6/4 (aa 45–68), has also been described as a target of proliferative responses

in CIN patients [35]. Another E6111–158 region was described previously as inducing proliferative responses in infected asymptomatic subjects or in patients with CIN3 [33,35], as well as E6127–141 peptide in healthy young women [36]. Similarly, peptides E7 43–77, E7 50–62 and E7 58–68, which are restricted by DR3, DR15 and DR17, respectively, were defined as epitopic peptides for CD4+ T cells [34,37,38], and E7 region 51–98, only including our E7/7 (aa 65–87) peptide, is also very immunogenic for proliferating T lymphocytes [22,23,31]. The characterization of E6 and E7 HPV-16 epitopes and the HLA restriction of their recognition by CD8+ T lymphocytes are more precise: E6 29–38, E7 11–20, E7 82–90 and E7 86–93 epitopes are presented by HLA-A2 [39–41], E6 80–88 and E7 44–52 by HLA-B18 [27] and E6 49–57 by HLA-A24 [42]. In women who cleared HPV-16 infection, cytotoxic T lymphocyte (CTL) responses are directed against epitopes located preferentially in the N-terminal half of the E6 protein (region 16–40) [43].