In November 2018, Simon Fraser University researchers along with a group of South African academics from the University of Kwa-Zulu Natal published a study that revealed how certain HIV-positive individuals possess immune cells that enable them to control their HIV viral load. This research provides further clues in the quest for developing an HIV vaccine, which is an epidemic that affects millions worldwide. The team plans to use their results to conduct future experiments that could lead to a more comprehensive understanding of a T-cell response associated with HIV.
The study, Dual HLA B*42 and B*81-reactive T cells receptors recognize more diverse HIV-1 Gag escape variants, was conducted from 2017–18, and the methods used in the study took approximately six years to establish, according to Gursev Anmole, a PhD candidate in molecular biology and biochemistry and one of the lead authors of the study.
In an email interview with The Peak, Anmole explained that the human immune system has immune cells called CD8+ T cells, also known as “killer T-cells.” Killer T-cells recognize virus particles (antigens) presented on virus-infected cells. Because of this unique ability, the CD8+ T cells are critical in destroying virus-infected cells.
When HIV infects a host cell, it expresses antigens on its cell surface via the human leukocyte antigen (HLA) protein, said Anmole. Killer T-cells have a receptor called the T-cell receptor (TCR) which identifies cells displaying the HLA protein. The killer T-cells destroy these cells to stop them from further damaging their host.
Uniquely, Anmole says, the HIV virus can mutate rapidly, which lets it evade this defensive mechanism to keep reproducing copies of itself and infecting nearby cells. However, some HIV-positive individuals possess CD8+ T cells that can still recognize and destroy these mutated HIV variants, keeping the concentration of HIV in their blood at a low amount.
“This recognition of mutated HIV variants by killer T-cells is made possible by “cross-reactive” TCR that can recognize mutated forms of an HIV antigen,” explained Anmole.
“Identifying and studying the characteristics of HIV-specific TCR in individuals that show HIV control can therefore help us identify mechanisms behind TCR-mediated HIV control, which in turn can be used to better design HIV vaccines and therapeutics,” he further added.
According to Anmole, the study analyzed two highly similar HLA proteins, HLA-B*81 and B*42. Both respond to the same HIV antigen, TL9.
Dr. Mark Brockman, who is an SFU health sciences professor and senior author of the study explained to SFU News that, “A person’s T cell “repertoire” is made up of a possible 20-100 million unique lineages of cells . . . To reduce the complexity of [this] study, the team examined [these two HLA variants].”
Anmole also noted that: “Since these HLAs are similar and the antigen they present is identical, [any] difference in HIV control between these groups may be [due to the fact that] B*81 individuals may have cross-reactive TCR able to recognize HIV escape variants while B*42 individuals may not.”
The researchers confirmed that individuals with B*81 could control their viral load much better than B*42-expressing individuals because they had cross-reactive TCR that were more sensitive to HIV variants, according to Anmole. This study demonstrated that some HIV-specific TCR recognize HIV escape variants better than others and that there may be a clinical benefit of possessing cross-reactive TCR, he further added.
When asked about the obstacles the team faced while conducting this study, Anmole shared: “Research is full of challenges as we are discovering new ideas . . . There were many challenges along the way, from complex assay design to late nights in the lab when things did not work and 7 a.m. Skype calls with our collaborators in Durban, South Africa!”
Anmole concluded the interview by saying the Brockman team will use the results from this experiment to conduct future experiments that include individuals with different HLA proteins who recognize different HIV antigens. This will lead to a more comprehensive understanding of a T-cell response associated with HIV control across a larger population.
With files from SFU News