Investigating the role of HLA class-1 polymorphisms within the Sub-Saharan African population, in the emergence, frequency, and persistence of SARS-CoV-2 variants.

Abstract

RATIONALE: Various studies have shown the ability of the cytotoxic T cell (by CD8+ T cells) immune response in disease control in the absence of neutralizing antibodies in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) convalescent individuals. Thus, illustrating the important role of the cytotoxic immune response in clearing coronavirus disease 2019 (COVID-19). Human Leukocyte Antigen molecules (HLA) present virus peptides to T cells during the activation of an immune response. However, only a few studies have looked at how the HLA allele repertoire of the infected population impacts immune escape, and none have looked at how the high HLA polymorphism in the Sub-Saharan African (SSA) population impacts the immune escape patterns in viruses circulating within this population.

AIM: The Aim of this study was to predict the HLA-mediated cytotoxic T cell immune escape mutations present in SARS-CoV-2 structural proteins isolated from SSA populations. The SARS- CoV-2 isolates for the study were analyzed from five SSA countries namely, Kenya, Democratic Republic of Congo, Nigeria, Ghana and Senegal to ask the question: Do HLA class-1 polymorphisms in SSA populations result in locally specific immune escape mutations in SARS- CoV-2?

ANALYSES AND FINDINGS: Immunoinformatic methods were used to predict potential HLA immune escape peptides for the SARS-CoV-2 structural proteins Spike, Nucleocapsid, Membrane and Envelope. SARS-CoV-2 sequences from the five SSA countries and a comparative sample of sequences from China, were used. All sequences downloaded from GISAID were subject to quality control, separated into their respective proteins and infection waves, and the potential HLA 9-mer motif containing peptides were predicted. Binding affinity for all the predicted peptides was measured using the NetMHCpan 4.1 software and results were further restricted to those peptides that had mutations occurring in more than one infection wave. The shortlisted results were summarized in tables and heatmaps. There were various escape mutations predicted for each of the structural proteins. The Spike and Nucleocapsid were the two proteins for which the greatest number of peptides were predicted respectively. The spike protein had between 7 to 37 escape peptides for the five countries, while the nucleocapsid ranged between 2 to 20for the five countries. The membrane protein ranged from 2 to 9 predicted peptides while the envelope ranged from 0 to 9 escape peptides for the five countries. However, due to a lack of HLA frequency data for the studied countries and high HLA admixture in the SSA population, associations between the HLA and the immune escape patterns could not be fully explained. Instead at country-level, clustering was observed for HLA alleles of the Spike protein between more geographically proximal countries indicating that HLA alleles do exert some selective pressure on the escape patterns.

CONCLUSION: In this study we were able to predict a substantial number of escape mutations circulating in the SSA population for the four structural proteins in SARS-CoV-2. While most of the high proportion predictions are mutations that have been reported in other studies as SARS- CoV-2 mutations, very few have been linked to T cell escape. Given the limited HLA allele frequency data we could not conclude if the HLA allele frequency in SSA is driving the mutations that occurred at high proportions. However, interesting pattern seen for a few of the escape mutations across countries was the emergence of variant peptides at high proportions but associated with HLA alleles that have a low frequency in the population. This could be an indication that these variants were introduced into the country and subsequently exposed to low selection pressure. In this study, we used large population genomic data to contribute towards understanding the extent of T cell immune escape mutations in SARS-CoV-2.