T Cell Recognition Diversity Linked to HIV Control

The immune system is the body’s best defense in fighting diseases like HIV and cancer.  Now, an international team of researchers is harnessing the immune system to provide new clues that may help efforts to produce an HIV vaccine.

SFU professor Mark Brockman and co-authors from the University of KwaZulu-Natal in South Africa have identified a connection between infection control and how well antiviral T cells respond to diverse HIV sequences.

Brockman explains that HIV adapts to the human immune system by altering its sequence to evade helpful antiviral T cells. “Development of an effective HIV vaccine will therefore require the generation of host immune responses that the virus cannot evade easily,” he says.

Brockman’s team developed new laboratory-based methods to identify antiviral T cells and to assess their ability to recognize diverse HIV sequences.

“T cells are white blood cells that are able to recognize foreign particles called peptide antigens,” says Brockman. "There are two major types of these cells, those that ‘help’ other cells of the immune system and those that kill infected cells and tumours.”

It sounds like a simple solution to identify those T cells that attack HIV antigens, but Brockman says three biological factors are critical to a T cell-mediated immune response — and all three are highly genetically diverse in the case of HIV infection.

For a T cell to recognize a peptide antigen, it must first be presented on the cell surface by human leukocyte antigen proteins (HLA). HLA genes are inherited and many thousands of possible variants exist in the human population, so every person’s response to infection is unique. In addition, HIV is highly diverse and evolves constantly during untreated infection, so the peptide antigen sequence can change.

Matching T cells against the HLA variants and HIV peptide antigens expressed in an individual is a critical step in the process that is routinely done for research, but Brockman says, “our understanding of T cell responses will be incomplete until we know more about the antiviral activity of individual T cells that contribute to this response.”

It is estimated that a person’s T cell “repertoire” is made up of a possible 20-100 million unique lineages of cells that can be distinguished by their T cell receptors (TCR), of which only a few will be important in responding to a specific antigen.

To reduce the complexity of their study, the team examined two highly related HLA variants, B81 and B42, that recognize the same HIV peptide antigen (TL9) but are associated with different clinical outcomes following infection.

By looking at how well individual T cells recognized TL9 and diverse TL9 sequence variants that occur in circulating HIV strains, they found that T cells from people who expressed HLA B81 recognized more TL9 variants compared to T cells from people who expressed HLA B42.

Notably, a group of T cells in some B42-expressing individuals displayed a greater ability to recognize TL9 sequence variants, and the presence of these T cells was associated with better control of HIV infection.

This study demonstrates that individual T cells differ widely in their ability to recognize peptide variants and suggests that these differences may be clinically significant in the context of a diverse or rapidly evolving pathogen such as HIV.

Much work needs to be done to create an effective vaccine. However, says Brockman, “comprehensive methods to assess the ability of T cells to recognize diverse HIV sequences, such as those reported in this study, provide critical information to help design and test new vaccine strategies.”

This article has been republished from materials provided by Simon Fraser University. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference
Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants. Funsho Ogunshola, Gursev Anmole, Rachel L. Miller, Emily Goering, Thandeka Nkosi, Daniel Muema, Jaclyn Mann, Nasreen Ismail, Denis Chopera, Thumbi Ndung’u, Mark A. Brockman & Zaza M Ndhlovu. Nature Communications volume 9, Article number: 5023 (2018), https://doi.org/10.1038/s41467-018-07209-7.