A rare human genetic make-up gives the best chance against HIV

People who inherit a rare genetic make-up responsible for immune responses to viruses have significantly slower HIV disease progression because the virus has not evolved to escape the immune system.

Each person has a limited selection of human leukocyte antigen (HLA) type 1 molecules on the surface of their cells and the precise combination of molecules determines the range of pathogens that an individual can respond to. HLA molecules are able to grab onto specific proteins that they are `programmed` to recognise and display these on the surface of cells as a signal that killer T cells are needed to eliminate the virally infected cell.

Previous research has shown that people with a broader range of class 1 HLA molecules are at lower risk of HIV disease progression, but the reasons for this advantage were not fully understood.

New research from the Swiss HIV Cohort, published in the August 17th edition of the Proceedings of the National Academy of Sciences, sheds new light on the mechanism.

The researchers found that HLA types associated with rapid disease progression often failed to elicit a killer T cell response, potentially because the HLA failed to bind and display the appropriate viral protein. Furthermore, rare HLA types were more likely to elicit an immune response than commonly occurring HLA types. The authors suggest that rare HLA types are advantageous because HIV variants that have mutated to evade recognition by rare HLAs should also be rare.

The researchers investigated cytotoxic T-lymphocyte (CTL) responses and HLA type in 84 patients participating in the Swiss-Spanish Intermittent Therapy Trial. Their risk of disease progression according to HLA type was assessed by using data from 850 US patients drawn from five cohorts with known dates of seroconversion who had been HLA-typed. (That study had shown that a single amino acid change in one HLA molecule, B35, significantly affected the rate of disease progression).

The researchers wanted to find out whether a patient with a particular class 1 HLA type could recognise a panel of peptides from an HIV-1 subtype consensus sequence. Each HLA molecule was tested against a different peptide panel so that researchers could be sure that a specific HLA molecule was responsible for an immune response to HIV. If patients responded positively by producing cytotoxic T-lymphocyte responses to HIV.

The researchers found a highly significant relationship between the capacity of an HLA type to elicit CTL responses and the risk of disease progression (p = 0.0007), with rare HLA types having a higher probability of recognising a broader range of HIV peptides and mounting a response to them.

The authors argue that rare HLA types are advantageous because HIV is less likely to have evolved to outwit CTLs targeted at more unusual peptides within its genetic sequence that might be recognised by rarer HLA types.

The implications of the findings for vaccine research are unclear. Much recent vaccine research has focussed on the need to encourage CTL responses to control HIV, but whether these findings will help in the identification of HIV sequences, or epitopes, that are more suitable for inlcusion in vaccine candidates remains to be seen.