Abstract
Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual's CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design as a supplement to vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.
Highlights
Since the Human Immunodeficiency Virus (HIV) was first identified, 77.3 million people have become infected of which 35.4 million people subsequently died [1]
We propose the use of the artificial neural network, NetMHCpan [17, 18] as a proxy to identify putative CD8 Tcell epitopes contained within the HIV transmitted founder virus (TFV) identified from the Protocol C clinical cohort of sub Saharan and East Africa
The analysis revealed distinct clusters of predicted Human Leukocyte Antigen (HLA) binding profiles which suggested that it was possible to identify a subgroup of Protocol C volunteers that were representative of the overall cohort HLA diversity
Summary
Since the Human Immunodeficiency Virus (HIV) was first identified, 77.3 million people have become infected of which 35.4 million people subsequently died [1]. Natural control of HIV viral load following the acute viral load burst is associated with a T-cell mediated response [5] and this suggests that a vaccine designed to raise T-cell responses may have efficacy if it is targeted to defined antigenic regions [6] including those with integral networked topology [7]. There are currently a number of T-cell vaccine candidates that utilize a variety of novel design approaches being tested in human clinical trials. The HIV Conserved vaccine (HIVCON) utilizes a conserved mosaic approach whereby regions of the proteome that have been identified as conserved within available databases are arranged in a specific regimen to both elicit T-cell responses to potential epitopes present within these regions, whilst limiting immunogenicity to the necessary joining or junctional regions [8]. There are pros and cons to all these approaches, but a potential caveat to utilizing conserved regions of the proteome is that historically pathogen diversity has been measured as the similarity or dissimilarity of sequences to each other, a vaccine design should factor in how this pathogen sequence conservation is viewed by the host immune system
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