New clues to controlling HIV found

Toronto: Researchers are harnessing the immune system to reveal new clues that may help produce a vaccine against the human immunodeficiency virus (HIV). The researchers from the Simon Fraser University (SFU) in Canada and the University of KwaZulu-Natal in South Africa identified a connection between infection control and how well antiviral T cells respond to diverse HIV sequences.

HIV adapts to the human immune system by altering its sequence to evade helpful antiviral T cells, they said. "So to develop an effective HIV vaccine, we need to generate host immune responses that the virus cannot easily evade," said Mark Brockman, a professor at SFU.

The team has developed new laboratory-based methods for identifying antiviral T cells and assessing their ability to recognise diverse HIV sequences. "T cells are white blood cells that can recognise foreign particles called peptide antigens," said Brockman.

"There are two major types of T cells -- those that 'help' other cells of the immune system, and those that kill infected cells and tumours," he said. Identifying the T cells that attack HIV antigens sounds simple, but Brockman said three biological factors are critical to a T cell-mediated immune response. In HIV infection, all three are highly genetically diverse.

He said for a T cell to recognise a peptide antigen, the antigen must first be presented on the cell surface by human leukocyte antigen proteins (HLA), which are are inherited. Since many thousands of possible HLA variants exist in the human population, every person responds differently to infection.

As HIV is highly diverse and evolves constantly during untreated infection, the peptide antigen sequence also changes. Matching T cells against the HLA variants and HIV peptide antigens expressed in an individual is a critical step in the routine research process.

"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," said Brockman. 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.

The team examined two highly related HLA variants (B81 and B42) that recognise the same HIV peptide antigen (TL9) but are associated with different clinical outcomes following infection.

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

A group of T cells in some B42-expressing individuals displayed a greater ability to recognise TL9 sequence variants. 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 recognise peptide variants and suggests that these differences may be clinically significant in the context of a diverse or rapidly evolving pathogen such as HIV.