Uncovering the Interplay Between CD8, CD4 and Antibody Responses to Complex Pathogens

Abstract

Vaccinia virus (VACV) was used as the vaccine strain to eradicate smallpox. VACV is still administered to healthcare workers or researchers who are at risk of contracting the virus, and to military personnel. Thus, VACV represents a weapon against outbreaks, both natural (e.g., monkeypox) or man-made (bioterror). This virus is also used as a vector for experimental vaccine development (cancer/infectious disease). As a prototypic poxvirus, VACV is a model system for studying host-pathogen interactions. Until recently, little was known about the targets of host immune responses, which was likely owing to VACVs large genome (>200 open reading frames). However, the last few years have witnessed an explosion of data, and VACV has quickly become a useful model to study adaptive immune responses. This review summarizes and highlights key findings based on identification of VACV antigens targeted by the immune system (CD4, CD8 and antibodies) and the complex interplay between responses. Keywords adaptive immunity; epitopes; immunodominant; protection; vaccinia virus Structure & taxonomy of poxviruses, & their relevance to human healthAmongst the viruses of relevance to human health, members of the poxvirus family have some of the largest viral genomes (ranging from 130 to 300 kb), with as many as 260 open reading frames (ORFs). All poxviruses replicate exclusively in the cytoplasm of their hosts and have an enveloped viral particle that carries the single, linear dsDNA genome. In general, the genes located in the center of the genome are relatively conserved among poxviruses and have essential molecular functions for replication and survival. By contrast, terminally located genes are more variable and encode proteins that interfere with the host response to infection (virulence factors) and determine host-range restriction [1].The poxviruses that infect vertebrate hosts comprise eight genera and, of these, the orthopox genus has the best-known members and also those most relevant to human health. The most prominent is variola virus (VARV), the causative agent of smallpox, and vaccinia virus (VACV), the vaccine used to prevent and eradicate this once dreaded disease. With smallpox conquered in the 1980s, attention was focused on the use of recombinant VACV as a vector for protein expression in the study of cancer and infectious disease vaccines [2]. A variety of strains of VACV have been used for these studies. The high rates of severe adverse events associated with the traditional smallpox vaccine led to the development of attenuated strains, exemplified by modified vaccinia virus Ankara (MVA). MVA was generated by extensive passaging of VACV Ankara on chicken embryo fibroblasts, resulting NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in the loss of several genes compared with the parental genome and loss of the ability to replicate in most mammalian cells, including primary human cells [3]. By contrast to the extreme attenuation of MVA, the most commonly used VACV strain for laborat...

Immunodominant “Asymptomatic” Herpes Simplex Virus 1 and 2 Protein Antigens Identified by Probing Whole-ORFome Microarrays with Serum Antibodies from Seropositive Asymptomatic versus Symptomatic Individuals

“…Of these, the arrays detected strong antibody signals against US6/gD (from both HSV-1 and -2) and UL48 of HSV-2, both of which are also CD4 ϩ target antigens. The overlap between the targets of antibody and CD4 ϩ cells, rather than CD8 ϩ cells, is also consistent with recent findings for vaccinia virus antigens (36,59,60). Further investigations of T-cell responses to ID-A-Ags versus ID-S-Ags may be needed to break new ground in our understanding of the protective versus pathogenic immune mechanisms against ocular, orofacial, and genital herpes.…”

“…The symptomatic and asymptomatic B-cell antigens identified in this study would certainly help speed up the identification of more symptomatic and asymptomatic T-cell antigens by serodiagnosing more symptomatic and asymptomatic individuals. In addition, many HSV and non-HSV antigens tend to contain both B-and T-cell epitopes (36,59,60). It was suggested previously that the most immunodominant B-cell antigens in HSV may be those of envelope proteins, such as the envelope glycoproteins UL27/gB and US6/gD (10).…”

Expression Profiling of the Intermediate and Late Stages of Poxvirus Replication

“…10C. The genes for top-ranked CD8 ϩ T cell antigens are predominantly in the early class, as noted previously (6,8,19). The genes for top-ranked CD4 ϩ T cell and B cell antigens are mostly synthesized after DNA replication but with a higher proportion in the intermediate than the late class (Fig.…”

“…A recent review summarized the VACV antigens recognized by CD8 ϩ T cells, CD4 ϩ T cells, and B cells (19). The distribution of these antigenic proteins in different expression classes is shown in Fig.…”

Predicting T cell recognition of MHC class I restricted neoepitopes

“…poxvirus infection, the vast majority of peptides that could in principle be recognized by the immune system in any context of immune exposure are not. 34,52 There are multiple aspects influencing immunodominance that impact which epitopes ultimately get recognized, ranging from variables associated with the antigen encoding the epitope (such as its abundance, cellular localization or kinetics of transcription), as well as conservation/cross-reactivity with other immune targets. These are also all relevant in the cancer setting, where expression level of the antigen itself, and the clonality of a mutation within the cancer cell population both impact the likelihood of detecting an immune response against it.…”