Haematopoietic stem-cell transplantation in an HIV endemic area: time to consider donors exposed to or living with HIV.

South Africa has more than 8 million people living with HIV. However, the number of patients undergoing haematopoietic stem-cell transplantation (HSCT) in South Africa is far below the target number. Donor numbers are insufficient to meet demand. Both HSCT and solid organ transplantation have proved successful in people living with HIV. Solid organ transplantation also has good outcomes when both donors and recipients have HIV. This Personal View explores the possible inclusion of people living with HIV and umbilical cord blood from HIV-negative infants exposed to HIV as donor sources for HSCT. Beyond the risk of HIV transmission, additional complications must be considered, such as delayed or inadequate immune reconstitution and an increased risk of haematological abnormalities and malignancies. Interactions between antiretroviral drugs and drugs used in the conditioning regimen, as well as the need to maintain virological suppression when gastrointestinal absorption deteriorates, are additional complicating factors. The process also requires more stringent ethical processes to be in place to minimise physical and emotional harm. However, in an HIV endemic country, people living with HIV or donors exposed to HIV must be considered as part of a multidisciplinary collaborative effort to provide more patients with the opportunity to have a life-saving HSCT.

Consequences of HIV infection in the bone marrow niche.

Dysregulation of the bone marrow niche resulting from the direct and indirect effects of HIV infection contributes to haematological abnormalities observed in HIV patients. The bone marrow niche is a complex, multicellular environment which functions primarily in the maintenance of haematopoietic stem/progenitor cells (HSPCs). These adult stem cells are responsible for replacing blood and immune cells over the course of a lifetime. Cells of the bone marrow niche support HSPCs and help to orchestrate the quiescence, self-renewal and differentiation of HSPCs through chemical and molecular signals and cell-cell interactions. This narrative review discusses the HIV-associated dysregulation of the bone marrow niche, as well as the susceptibility of HSPCs to infection by HIV.

Genetic Associations with Coronavirus Susceptibility and Disease Severity.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global public health emergency, and the disease it causes is highly variable in its clinical presentation. Host genetic factors are increasingly recognised as a determinant of infection susceptibility and disease severity. Several initiatives and groups have been established to analyse and review host genetic epidemiology associated with COVID-19 outcomes. Here, we review the genetic loci associated with COVID-19 susceptibility and severity focusing on the common variants identified in genome-wide association studies.

Open access and its potential impact on public health - A South African perspective.

Traditionally, access to research information has been restricted through journal subscriptions. This means that research entities and individuals who were unable to afford subscription costs did not have access to journal articles. There has however been a progressive shift toward electronic access to journal publications and subsequently growth in the number of journals available globally. In the context of electronic journals, both open access and restricted access options exist. While the latter option is comparable to traditional, subscription-based paper journals, open access journal publications follow an "open science" publishing model allowing scholarly communications and outputs to be publicly available online at no cost to the reader. However, for readers to enjoy open access, publication costs are shifted elsewhere, typically onto academic institutions and authors. SARS-CoV-2, and the resulting COVID-19 pandemic have highlighted the benefits of open science through accelerated research and unprecedented levels of collaboration and data sharing. South Africa is one of the leading open access countries on the African continent. This paper focuses on open access in the South African higher education research context with an emphasis on our Institution and our own experiences. It also addresses the financial implications of open access and provides possible solutions for reducing the cost of publication for researchers and their institutions. Privacy in open access and the role of the Protection of Personal Information Act (POPIA) in medical research and secondary use of data in South Africa will also be discussed.

The NESHIE and CP Genetics Resource (NCGR): A database of genes and variants reported in neonatal encephalopathy with suspected hypoxic ischemic encephalopathy (NESHIE) and consequential cerebral palsy (CP).

Neonatal encephalopathy (NE) with suspected hypoxic ischaemic encephalopathy (HIE) (NESHIE) is a complex syndrome occurring in newborns, characterised by altered neurological function. It has been suggested that genetic variants may influence NESHIE susceptibility and outcomes. Unlike NESHIE, for which a limited number of genetic studies have been performed, many studies have identified genetic variants associated with cerebral palsy (CP), which can develop from severe NESHIE. Identifying variants in patients with CP, as a consequence of NESHIE, may provide a starting point for the identification of genetic variants associated with NESHIE outcomes. We have constructed NCGR (NESHIE and CP Genetics Resource), a database of genes and variants reported in patients with NESHIE and CP (where relevant to NESHIE), for the purpose of collating and comparing genetic findings between the two conditions. In this paper we describe the construction and functionality of NCGR. Furthermore, we demonstrate how NCGR can be used to prioritise genes and variants of potential clinical relevance that may underlie a genetic predisposition to NESHIE and contribute to an understanding of its pathogenesis.

Coronavirus Host Genetics South Africa (COHG-SA) database-a variant database for gene regions associated with SARS-CoV-2 outcomes.

The SARS-CoV-2 virus is responsible for the COVID-19 global public health emergency, and the disease it causes is highly variable in its clinical presentation. Clinical phenotypes are heterogeneous both in terms of presentation of symptoms in the host and response to therapy. Several studies and initiatives have been established to analyse and review host genetic epidemiology associated with COVID-19. Our research group curated these articles into a web-based database using the python application-server framework Django. The database provides a searchable research tool describing current literature surrounding COVID-19 host genetic factors associated with disease outcome. This paper describes the COHG-SA database and provides an overview of the analyses that can be derived from these data.

High Resolution HLA ∼A, ∼B, ∼C, ∼DRB1, ∼DQA1, and ∼DQB1 Diversity in South African Populations.

Background: Lack of HLA data in southern African populations hampers disease association studies and our understanding of genetic diversity in these populations. We aimed to determine HLA diversity in South African populations using high resolution HLA ∼A, ∼B, ∼C, ∼DRB1, ∼DQA1 and ∼DQB1 data, from 3005 previously typed individuals. Methods: We determined allele and haplotype frequencies, deviations from Hardy-Weinberg equilibrium (HWE), linkage disequilibrium (LD) and neutrality test. South African HLA class I data was additionally compared to other global populations using non-metrical multidimensional scaling (NMDS), genetic distances and principal component analysis (PCA). Results: All loci strongly (p < 0.0001) deviated from HWE, coupled with excessive heterozygosity in most loci. Two of the three most frequent alleles, HLA ∼DQA1*05:02 (0.2584) and HLA ∼C*17:01 (0.1488) were previously reported in South African populations at lower frequencies. NMDS showed genetic distinctness of South African populations. Phylogenetic analysis and PCA clustered our current dataset with previous South African studies. Additionally, South Africans seem to be related to other sub-Saharan populations using HLA class I allele frequencies. Discussion and Conclusion: Despite the retrospective nature of the study, data missingness, the imbalance of sample sizes for each locus and haplotype pairs, and induced methodological difficulties, this study provides a unique and large HLA dataset of South Africans, which might be a useful resource to support anthropological studies, disease association studies, population based vaccine development and donor recruitment programs. We additionally provide simulated high resolution HLA class I data to augment the mixed resolution typing results generated from this study.

Single-Cell Transcriptome Analysis of Human Adipose-Derived Stromal Cells Identifies a Contractile Cell Subpopulation.

The potential for human adipose-derived stromal cells (hASCs) to be used as a therapeutic product is being assessed in multiple clinical trials. However, much is still to be learned about these cells before they can be used with confidence in the clinical setting. An inherent characteristic of hASCs that is not well understood is their heterogeneity. The aim of this exploratory study was to characterize the heterogeneity of freshly isolated hASCs after two population doublings (P2) using single-cell transcriptome analysis. A minimum of two subpopulations were identified at P2. A major subpopulation was identified as contractile cells which, based on gene expression patterns, are likely to be pericytes and/or vascular smooth muscle cells (vSMCs).

Perspectives on establishing a public cord blood inventory in South Africa.

The South African population is highly diverse, both ethnically and genetically. This diversity is particularly true for the African ancestry and various mixed ancestry population groups. These groups are under-represented in national and international bone marrow and peripheral blood donor registries, making it challenging to identify HLA-matched and mismatched unrelated donors when patients from these groups require allogeneic hematopoietic stem and progenitor cell transplantation. In most high-income countries, banked cord blood (CB) units provide an attractive source of hematopoietic progenitor cells for genetically diverse populations. SA does not have a public CB inventory, leaving many patients without access to this important treatment modality. Haploidentical transplantation provides an alternative. In recent years, the use of post-transplant cyclophosphamide has significantly reduced the incidence of graft-versus-host disease after haploidentical transplantation and has improved transplantation outcomes. However, it is difficult to identify suitable haploidentical donors in SA because of family disruption and a high prevalence of HIV. Here the authors provide a brief historical overview of the ethnic and genetic diversity of the country and region. The authors provide a southern African perspective on HLA diversity, consider the allogeneic hematopoietic stem and progenitor cell transplantation landscape and explore the need to establish a public CB bank (CBB) in SA. The health policy and regulatory frameworks that will impact on a CBB in the country SA are also explored. Finally, the authors discuss several matters we believe require attention when considering the establishment of a sustainable public CBB in the South African context.

A COVID-19 Vaccine: Big Strides Come with Big Challenges.

As of 8 January 2021, there were 86,749,940 confirmed coronavirus disease 2019 (COVID-19) cases and 1,890,342 COVID-19-related deaths worldwide, as reported by the World Health Organization (WHO). In order to address the COVID-19 pandemic by limiting transmission, an intense global effort is underway to develop a vaccine against SARS-CoV-2. The development of a safe and effective vaccine usually requires several years of pre-clinical and clinical stages of evaluation and requires strict regulatory approvals before it can be manufactured in bulk and distributed. Since the global impact of COVID-19 is unprecedented in the modern era, the development and testing of a new vaccine are being expedited. Given the high-level of attrition during vaccine development, simultaneous testing of multiple candidates increases the probability of finding one that is effective. Over 200 vaccines are currently in development, with over 60 candidate vaccines being tested in clinical trials. These make use of various platforms and are at different stages of development. This review discusses the different phases of vaccine development and the various platforms in use for candidate COVID-19 vaccines, including their progress to date. The potential challenges once a vaccine becomes available are also addressed.

SARS-CoV-2 Variants, Vaccines, and Host Immunity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy to protect the vulnerable, and can be established through immunity from past infection or vaccination. Whether SARS-CoV-2 infection results in the development of a reservoir of resilient memory cells is under investigation. Vaccines have been developed at an unprecedented rate and 7 408 870 760 vaccine doses have been administered worldwide. Recently emerged SARS-CoV-2 variants are more transmissible with a reduced sensitivity to immune mechanisms. This is due to the presence of amino acid substitutions in the spike protein, which confer a selective advantage. The emergence of variants therefore poses a risk for vaccine effectiveness and long-term immunity, and it is crucial therefore to determine the effectiveness of vaccines against currently circulating variants. Here we review both SARS-CoV-2-induced host immune activation and vaccine-induced immune responses, highlighting the responses of immune memory cells that are key indicators of host immunity. We further discuss how variants emerge and the currently circulating variants of concern (VOC), with particular focus on implications for vaccine effectiveness. Finally, we describe new antibody treatments and future vaccine approaches that will be important as we navigate through the COVID-19 pandemic.

Side Population: Its Use in the Study of Cellular Heterogeneity and as a Potential Enrichment Tool for Rare Cell Populations.

There is still much to learn about the cells used for cell- and gene-based therapies in the clinical setting. Stem cells are found in virtually all tissues in the human body. As a result, cells isolated from these tissues are a heterogeneous population consisting of various subpopulations including stem cells. Several strategies have been used to isolate and define the subpopulations that constitute these heterogeneous populations, one of which is the side population (SP) assay. SP cells are identified by their ability to efflux a fluorescent dye at a rate that is greater than the main cell population. This elevated rate of dye efflux has been attributed to the expression of members of the ATP-binding cassette (ABC) transporter protein family. SP cells have been identified in various tissues. In this review, we discuss the research to date on SP cells, focussing on SP cells identified in haematopoietic stem cells, adipose-derived stromal cells, and dental pulp.

Human Leukocyte Antigen Diversity: A Southern African Perspective.

Despite the increasingly well-documented evidence of high genetic, ethnic, and linguistic diversity amongst African populations, there is limited data on human leukocyte antigen (HLA) diversity in these populations. HLA is part of the host defense mechanism mediated through antigen presentation to effector cells of the immune system. With the high disease burden in southern Africa, HLA diversity data is increasingly important in the design of population-specific vaccines and the improvement of transplantation therapeutic interventions. This review highlights the paucity of HLA diversity data amongst southern African populations and defines a need for information of this kind. This information will support disease association studies, provide guidance in vaccine design, and improve transplantation outcomes.

HLA typing: Conventional techniques v. next-generation sequencing.

BACKGROUND: The large number of population-specific polymorphisms present in the HLA complex in the South African (SA) population reduces the probability of finding an adequate HLA-matched donor for individuals in need of an unrelated haematopoietic stem cell transplantation (HSCT). Next-generation sequencing (NGS) has numerous advantages compared with conventional typing techniques. OBJECTIVE: To evaluate whether NGS can provide any additional value over conventional techniques in the SA context for the purpose of HSCT and cord blood banking. METHODS: HLA genotyping was performed using NGS on 20 samples that had previously been HLA typed by conventional methods to evaluate whether NGS might provide any additional value over conventional HLA determination techniques. RESULTS: NGS of routinely sequenced loci and exons yielded accurate genotypes for 98.5% of the five loci of interest, compared with 98% when additional exons were included. CONCLUSION: The study shows that the additional value of NGS over conventional techniques is limited, and unless done on a large scale to reduce cost may not be appropriate in SA at this stage in the context of HSCT and cord blood banking.