Identifying elite controllers: a genomic study of South African individuals with HIV
Veron Ramsuran (right) is a Professor at the University of KwaZulu-Natal (UKZN; South Africa) specializing in the association between human genetics and infectious diseases. Veron completed his PhD and postdoc in the USA before returning to South Africa, where he is now the Principal Investigator of HIV, tuberculosis and other infectious disease studies.
Rizwana Mia (left) is the Senior Program Manager of strategic health innovation partnerships at the South African Medical Research Council (SAMRC; Cape Town, South Africa) and Vice Chair of The International Consortium for Personalised Medicine (ICPerMed). Rizwana studied genetics before joining a startup developing monoclonal antibodies. From there, Rizwana moved into conducting feasibility studies, technology transfers of new innovations into South Africa, technical commercial due diligence and intellectual property due diligence. She joined the SAMRC in 2015, where she started the Precision Medicine Program and SAMRC Genomics Centre.
The UKZN and the SAMRC have teamed up to work on the HIV Host Genome Project, which investigates how specific mutations present in certain individuals with HIV could act as protective mechanisms, facilitating the design of future therapies. This project has also partnered with MGI (Shenzhen, China), a company that provides real-time, multi-omics digital equipment for precision medicine, to utilize their large-scale genomic sequencing infrastructure. This allowed the researchers to initiate, for the first time, a large-scale genomic investigation into the many South African individuals living with HIV and the few who can control it.
The HIV-positive population in South Africa
A large population in South Africa – approximately 7.8 million people as of 2022 – has HIV, making it a key influencer of South Africa’s population dynamics. However, much research into HIV genomes, and human genomes generally, has been conducted in European populations. Despite having the largest genetic diversity in the world, African human genomes have been neglected. The researchers started the HIV Host Genome Project to remedy this situation, setting out to sequence an entire cohort of individuals of African descent with HIV. In doing so, they were hoping to identify individuals with protective phenotypes – known as controllers and elite controllers – to understand the genetic basis of this innate HIV protection and how it may inform future therapies.
Controllers are individuals who can sustain very low viral loads for an extended period, while elite controllers can control the virus to undetectable viral load levels for an extended period. Elite controllers do this without taking antiretroviral therapy and without showing any signs of getting sick or demising from the disease. A significant part of the researchers’ large-scale sequencing effort has been focused on comparing these controllers with individuals rapidly progressing with the virus in the hopes of identifying what makes controllers genetically different. Their data has highlighted that elite controllers possess unique genetic characteristics that are not present in other individuals.
Although elite controllers have been studied previously in European populations, these individuals have accounted for less than 1% of HIV-infected individuals. Due to the high prevalence of HIV in South Africa, the researchers have access to more samples and therefore more opportunities to identify controllers and elite controllers. Additionally, they have found that sequencing family members of their HIV-positive cohort has provided a better indication of the variation that arises within these familial structures by eliminating heterogeneity. However, this isn’t always easy as family structures can differ, with some HIV-positive individuals only having one accessible relation, making the evaluation and interpretation of genetic data more difficult. Rizwana explained that familial sequencing can inform not only greater HIV research, but also the SAMRC’s ambition to create a population reference for their precision medicine ecosystem down the line.
Elite controllers aren’t easy to find
Despite the percentage of elite controllers being higher in South Africa than in certain European populations, that doesn’t make them any easier to find. Elite controllers are extremely rare and identifying them has become even more difficult since medical guidelines surrounding HIV diagnosis changed around the world. Now, when a person is identified as being HIV positive, doctors must initiate antiretroviral therapy immediately. If a person is on antiretroviral therapy, the researchers don’t know if individuals are suppressing the virus because of their innate immune genes or because of the antiretroviral therapy. Therefore, the only way to find out if someone is an elite controller is to have them halt treatment for an extended period and monitor their symptoms.
“Previously, the guidelines were that if an individual was infected with HIV, they had to have a CD4 count below a certain threshold to receive antiretroviral therapy. It was easier for us to find elite controllers within this framework. Because of the new framework, I want to make clear how difficult it is to identify elite controllers. Even though there should be more statistically, they’re still very rare and hard to find,” explained Veron.
What it could take to create a controller
Veron and colleagues are conducting whole human genome sequencing using MGI’s DNBSEQ-G400 platform, robotic systems and an accelerator software, called MegaBOLT, that accelerates the processing of data that comes off the MGI machines. These scaled workflow technologies are facilitating the study of genetic mutations in an African population, which hasn’t been well studied previously. Veron commented, “the idea is that there could be a whole range of new mutations that we don’t know about that could be playing a role in this environment. We didn’t want to do a genome-wide association study, which looks at approximately 1–2 million mutations across the entire human genome; we wanted to look at the entire human genome itself and see what is novel in our South African controller populations.” The team was then able to analyze the genetic differences between the controller phenotype and the progressive, virally susceptible phenotype. Their analysis focused on both identifying novel polymorphisms that might be associated with the disease as well as existing polymorphisms associated with HIV, which act as controls and validation measures.
In their previous studies, the team identified specific mutations within certain human genes responsible for showing protection in a subset of controller individuals. These genes were involved at various stages of HIV’s life cycle. For example, HIV entry into the host human cell is an important stage for the virus; mutations within the viral entry gene show protection against HIV as the mutation leads to the expression of nonfunctional viral receptors, called chemokine coreceptor 5 (CCR5). Amongst individuals of Caucasian descent, a 32 base pair deletion in this gene makes a person completely resistant to HIV infection. This mechanism of protection was shown to cure HIV in a patient in Berlin (Germany), Timothy Brown, following a stem cell transplant from a CCR5 Δ32 homozygote individual. Timothy lived for an extended period without any detectable HIV; he is the only person to have been cured of HIV.
CCR5 Δ32 is not prevalent amongst individuals of African descent; however, there are specific markers that have been published previously by Veron’s group and other researchers that have shown alternative human genetic factors associated with protection. Using these known mutations as potential controls, Veron and colleagues conducted their analysis using the MGI sequencer.
Harnessing what we know about elite controllers for future therapeutics
The current project serves as a base upon which further research is required. As discussed, elite controllers are difficult to identify under current medical protocols, which slows research progression. This combined with the global lack of genomic information on HIV patients of African descent makes the development of newer treatments that are relevant to this population even more challenging. “I think that this research can form a baseline for us to explore these avenues. In the future, this sort of work could be utilized to develop more relevant treatments according to the mutations that are present within our population genomes and the host–viral interaction as well,” commented Rizwana.
By understanding the population better and the mechanisms of infection within this population group, the team is adequately positioned to one day develop better therapeutics and sustainably address the burden of disease. What’s more, the research will hopefully lead to more personalized and holistic treatment approaches for a range of diseases for individuals in Africa.
The key outcome of the HIV Host Genome Project is to understand protective mechanisms in a population that’s infected with the virus with the highest burden of disease. Previously, most research has been conducted on European populations; however, the mutations associated with the disease in Caucasian individuals don’t always translate to African populations. Now, researchers can directly study HIV-positive individuals of African descent on the genomic level, gaining greater insight into what these patients need. By identifying elite controllers, they are also hopeful that they can develop drugs or human therapies that mimic what their genetic makeup naturally does, curbing the growing problem of antiretroviral resistance. This idea is gaining traction in the Western world where mRNA-based vaccines are being developed: “We’re looking at CRISPR, which is a gene-editing tool that helps us to edit individuals and protect against diseases, as a potential therapeutic avenue. We’re hoping this study pushes us in that direction, helping us gain a better understanding of what therapies will look like in the future.”
Laying the foundation for genomics research initiatives in Africa
The HIV Host Genome Project has been the first large-scale human genome project conducted within Africa itself. It has paved the way for future research, constructing pipelines and infrastructure for conducting human genome sequencing studies for HIV and other diseases, such as tuberculosis. It has also highlighted any problem areas or roadblocks that need to be considered. For the researchers, the roadblock they’ve discovered is in the analysis. Veron shared, “The bioinformatics skillset is not something we have readily available, especially when looking at whole human genome analysis in this environment. There is no template because it’s never been done before in this environment. What we’ve done is send various individuals within our group to train overseas and bring the knowledge back, or we’ve contracted international partners to work with us to help with analysis. I think this is still a problem; we must expand our data analysis toolbox so that we can do this better in the future. And I think that was a huge stumbling block for us in this project.”
Rizwana concluded, “Developing more knowledge on our population is pertinent for any genomic studies analyzing any disease entity. The ultimate goal is that we create a national genome program. We must put in place sustainable capacity development for tertiary analysis, especially in bioinformatics. The project has given us a very nice context for developing that next phase of a national program and being able to address those shortfalls and empower our communities.” Rizwana is currently trying to coordinate a South African Human Genome Program that will sequence 110,000 humans to create a population genomic archive that can be used to inform future studies, therapeutics and health in South Africa.
The power of partnerships
The HIV Host Genome Project – a collaborative effort between the UKZN, the SAMRC, MGI and the patient cohorts themselves – is built on partnerships. Veron shared, “I think the most important thing about research is partnerships. We realized, especially during COVID, that doing things in isolation doesn’t work. We must collaborate, and that’s what we decided to do. This trifecta collaboration between SAMRC, MGI and UKZN has enabled us to have the facility we need to conduct research on a disease that is highly relevant locally in South African communities.”
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect the views of BioTechniques or Taylor & Francis Group.
