Elite controllers could hold the key to treating HIV

Although South Africa has the largest number of people living with HIV worldwide, strides have been made in controlling the epidemic. Now, equipped with MGI’s advanced sequencing tools and technologies, researchers from the South African Medical Research Council (SAMRC) and University of KwaZulu-Natal (UKZN) are inching closer to finding the answer to the natural control of HIV infection.

According to the Human Sciences Research Council, in 2022 there were approximately 7.8 million people afflicted with HIV in South Africa. Yet despite having the largest genetic diversity in the world, African human genome sequences represent the lowest of all the human genomes that have been sequenced worldwide. There is therefore a dire need to leverage genomics to back up and scale targeted intervention programs to put more people living with HIV on effective treatment.

Global investigations into HIV are particularly interested in ‘elite controllers’ (ECs) — a rare group of HIV‐1‐positive individuals whose immune systems can seemingly suppress the infection from developing without taking antiretrovirals (ARVs). For every 200 people living with HIV, around one may be an elite controller (0.5%). In South Africa, with its high rate of HIV infection, the prevalence of ECs also appears to be higher. By ‘unmasking’ the secrets of ECs through research, clues can be revealed and new therapies potentially developed to benefit broader groups of people living with the disease.

In order to identify the polymorphism and mutations within individuals of African descent, and how they are associated with HIV disease progression, Dr Veron Ramsuran, Associate Professor at UKZN, and Professor Thumbi Ndung’u, Director for Basic & Translational Science at the Africa Health Research Institute, joined with SAMRC, MGI and local South African clinics in 2019 to take their 20+ years of work in EC research to the next level using whole-genome sequencing.

“The HIV Host Genome project was started at the same time as we launched SAMRC’s African Genomics Centre in Cape Town with the support from MGI,” said project co-investigator Rizwana Mia. “The partnership saw MGI putting down a high-throughput sequencing workflow, and assisted us with the specialised scaled infrastructure design in our lab. This was at a time when there was no real infrastructure for large-scale next generation sequencing in Africa.

“More importantly, by moving our laboratory workflow to scale, we are hoping to develop genomic research to address this quadruple burden of disease that South Africa faces. Our project looks at a unique cohort of patients that have the ability to control the HIV virus to ascertain how disease progresses and the host-directed mechanisms for innate immune control. In addition, we included family sets to help us better understand the relationship between paediatric non-progressors and their parents who are also HIV positive, to uncover and genetic differences that may contribute to host immune control of HIV.”

As part of the project, MGI’s DNBSEQ sequencing technology, platforms and workflow are playing an instrumental role. Relying on DNBSEQ’s high accuracy, quick turnaround time and cost-effectiveness, researchers are able to generate quality data for analysing different HIV genotypes and identifying potential immunological mechanisms associated with ECs. Indeed, through collaborative efforts, the team has made significant progress in uncovering crucial genetic insights into the study of ECs.

“We’ve identified new genes and polymorphism that are playing a role with HIV disease through new data generated from whole genome sequencing,” said Ramsuran, the principal investigator on the project. “Traditionally, there is a list of mutations or genes that are known to associate with HIV, yet they are largely based on studies on Caucasian populations. Our HIV research is adding to the general pool of knowledge pertaining to individuals of African descent, which will thereby inform new treatment and new vaccine opportunities.”

“What’s important is also understanding how drugs interact with the individual. We’ve found in the past that certain polymorphism is associated with drug metabolism in genes. Building on this understanding of drugs in combination with the genetics of the individual, we can develop prediction tools to inform clinicians on drug type or dosage depending on the presence of the polymorphism to facilitate a more rapid metabolism of the drug.”

Through infrastructure and technical support from MGI, SAMRC has been refining the science of genomics for personalised medicine, besides HIV, to benefit Africa’s diverse gene pool. Notably, the establishment of the SAMRC Genomics Centre has enhanced South Africa’s ability to sequence, analyse and store human genomes, unlocking a new level of cutting-edge research.

Given South Africa’s diverse population, limited human genomics data and significant healthcare burden from diseases such as HIV, understanding pathogenesis and inherent mutations is important for implementing targeted treatments and public health programs. With its low sequencing cost, high-quality data and efficient all-in-one workflows, MGI will continue to drive progress in studying rare HIV phenotypes, which holds great promise in advancing the development of targeted interventions and cures — not only for HIV, but many other diseases.

“Looking at the genetic variation and its impact on HIV is a game changer, because it will shed light on some of the best immune responses that can be generated against the HIV virus,” Ndung’u said. “And actually, this knowledge will be widely applicable and could have an impact on other diseases — infectious and non-infectious — as well as their drug interventions. It will make sure that Africans, just like everybody else, are at the centre of drug and vaccine development.”

Image credit: iStock.com/Artem_Egorov