Abstract
Identification of HLA-restricted CD8+ T cell epitopes is important to study RSV-induced immunity and illness. We algorithmically analyzed the sequence of the fusion protein (F) of respiratory syncytial virus (RSV) and generated synthetic peptides that can potentially bind to HLA-A*0201. Four out of the twenty-five 9-mer peptides tested: peptides 3 (F33–41), 13 (F214–222), 14 (F273–281), and 23 (F559–567), were found to bind to HLA-A*0201 with moderate to high affinity and were capable of inducing IFN-γ and IL-2 secretion in lymphocytes from HLA-A*0201 transgenic (HLA-Tg) mice pre-immunized with RSV or recombinant adenovirus expressing RSV F. HLA-Tg mice were immunized with these four peptides and were found to induce both Th1 and CD8+ T cell responses in in vitro secondary recall. Effector responses induced by these peptides were observed to confer differential protection against live RSV challenge. These peptides also caused better recovery of body weight loss induced by RSV. A significant reduction of lung viral load was observed in mice immunized with peptide 23, which appeared to enhance the levels of inflammatory chemokines (CCL17, CCL22, and IL-18) but did not increase eosinophil infiltration in the lungs. Whereas, significant reduction of infiltrated eosinophils induced by RSV infection was found in mice pre-immunized with peptide 13. Our results suggest that HLA-A2-restricted epitopes of RSV F protein could be useful for the development of epitope-based RSV vaccine.
Highlights
Respiratory syncytial virus (RSV) induces respiratory disease in children and the elderly around the globe [1,2,3], and till there is no effective prophylactic vaccine available against RSV infection
The relative mean fluorescence intensity (MFI) obtained from the positive control (PC) peptide derived from Epstein-Barr virus capsid protein (GLC-9, a previously defined HLA-A*0201-restricted cytotoxic T lymphocytes (CTLs) epitope) was twofold (MFI = 1.96) compared to the baseline MFI = 1 obtained from the negative control (NC) treated with an unrelated peptide HCV C55-74
We found that peptide immunization did not lead to a profound increase in infiltrated pulmonary CD8+ T lymphocytes upon RSV challenge (Fig. 5B); CD8+ T cell numbers were lower when immunized with the peptides 13, 14, or 23, compared to vehicle immunization
Summary
Respiratory syncytial virus (RSV) induces respiratory disease in children and the elderly around the globe [1,2,3], and till there is no effective prophylactic vaccine available against RSV infection. Previous attempts in developing a vaccine using formalin-inactivated RSV failed because it exacerbated the disease upon subsequent infection in some cases [4]. Adoptive transfer of CD8+ CTLs offers protection to recipient BALB/c mice from subsequent infection by limiting viral replication in vivo [5], and inhibits RSV vaccine induced pulmonary eosinophilia [6]. This function is dependent on the numbers of CD8+ CTLs in the lungs to inhibit pulmonary eosinophilia as well as the production of type 2 helper T cell (Th2) associated chemokines in mice [7].
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