Structural and Nonstructural Viral Proteins Are Targets of T-Helper Immune Response against Human Respiratory Syncytial Virus

Abstract

Newly synthesized HLA class II molecules from antigenpresenting cells associate with the class II invariant chain (Ii). These complexes are eventually transported to specialized endosomal compartments where the Ii is progressively proteolyzed until only a fragment known as the class-II-associated invariant chain peptide (CLIP) 1 remains bound in the HLA class II peptide-binding groove to prevent it from binding to cellular peptides or pathogen peptides from the endogenous pathways. Interaction of HLA class II/CLIP complexes with the accessory molecule HLA-DM induces conformational changes in HLA class II molecules. Additionally, the release of CLIP results in peptide-receptive HLA class II molecules. This compartment fuses with a late endosome that contains exogenous proteins and/or viral particles that were previously endocytosed. Thus, the binding of antigen-processed peptides of different lengths, but with specific major anchor residues that can be deeply accommodated into specific pockets of the antigen recognition site of the HLA class II molecule, produces the stabilization of the nascent HLA class II/peptide complexes and allows for their subsequent transport to the cell membrane where they are exposed for T cell recognition (1).Human respiratory syncytial virus (HRSV) (2), which is included in the Paramyxoviridae family of the Mononegavirales order, presents a single-stranded, negative-sense RNA genome that codes for 11 proteins. This enveloped pneumovirus causes repeat infections throughout life, and although in healthy adults mild infections are generally reported, the health risk in infected pediatric, immunocompromised, and elderly populations is much more serious. HRSV is the main cause of hospitalization for bronchiolitis and pneumonia in infants and young children, with infection rates approaching 70% in the first year of life (3). Worldwide, at least 3.4 million hospital admissions each year are associated with severe HRSV disease, and the global mortality rate was estimated at more than a quarter of a million deaths in 2010, mainly in developing countries (4).The immune mechanisms involved in HRSV disease and protection are not completely understood; however, it is known that infection induces mucosal and systemic humoral and cellular responses. Studies evaluating CD4 ϩ and CD8 ϩ T-lymphocyte subsets individually or together showed that both effector MHC class I-and helper MHC class II-restricted cellular responses are particularly important in clearing infections (5). Previously, some HRSV epitopes that are restricted by different HLA class II molecules were identified using T cells from seropositive individuals (6 -9). However, these experiments were performed with overlapping synthetic pepFrom the ‡Centro Nacional

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

“…Viral peptides were among those identified in the earliest studies of naturally processed MHC‐II peptides , but peptide elution and mass spectrometry have not been applied commonly to problems of MHC‐II epitope discovery. The method has been used to identify MHC‐II epitopes derived from measles and vaccinia in humans, from HRSV in DR4‐transgenic mice , and from Chlamydia in mice . As in these previous studies, we found that peptide elution from virus‐infected cells was a very efficient way to identify bona fide T‐cell epitopes: each one of the HHV‐6B core epitopes identified by elution and mass spectrometry was recognized by circulating CD4 T cells from immune donors with matched HLA‐DR alleles.…”

“…This method has been used to identify MHC‐I epitopes from several human pathogens including many viruses (Epstein‐Barr , measles , vaccinia , influenza , dengue , West Nile , hepatitis C , hepatitis B , and human respiratory syncytial virus (HRSV) ). Naturally processed and presented MHC‐II epitopes for Epstein‐Barr , measles , vaccinia , and HRSV have also been reported. Our objective in this work was to use this approach to identify naturally processed and presented peptides derived from HHV‐6B, and to characterize the CD4 T‐cell response to these epitopes.…”

Anti-COVID-19 multi-epitope vaccine designs employing global viral genome sequences

“…However, the multi-epitopes do contain strong HLA superfamily allele binding regions from structural as well as non-structural proteins. These structural, as well as non-structural proteins, play an important part in viral assembly and attachment and specific immune responses against them are required to combat the infection (Lorente et al, 2016;Astuti, 2020). Despite the numerous benefits associated with this computational study, experimental validation is required to verify these results.…”

Immunoinformatic identification of B cell and T cell epitopes in the SARS-CoV-2 proteome

“…There is currently very little known regarding which epitopes in the SARS-CoV-2 proteome are recognized by the human immune system, although a limited number of studies have recently reported a broad spectrum of cellular immune responses against the structural and non-structural proteins from SARS-CoV-2 among convalescent subjects 25 – 27 . Studies of SARS-CoV immune responses suggest that both cellular and humoral responses against structural proteins mediate protection against disease 19 , 22 , 28 – 30 , and it is likely that cellular immune responses against non-structural viral proteins also play a key role in orchestrating protective antiviral immunity 31 – 33 . In lieu of biological data, immunoinformatic algorithms can be employed to predict peptide epitopes based on amino acid properties and known human leukocyte antigen (HLA) binding profiles 34 – 36 .…”