PLoS One. 2012;7(10):e47799.

Co-operative additive effects between HLA alleles in control of HIV-1.

Matthews PC, Listgarten J, Carlson JM, Payne R, Huang KH, Frater J, Goedhals D, Steyn D, van Vuuren C, Paioni P, Jooste P, Ogwu A, Shapiro R, Mncube Z, Ndung’u T, Walker BD, Heckerman D, Goulder PJ.

Department of Paediatrics, University of Oxford, Oxford, United Kingdom.



BACKGROUND: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles–irrespective of linkage disequilibrium–function co-operatively.

METHODOLOGY/PRINCIPAL FINDINGS: We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03).

CONCLUSIONS/SIGNIFICANCE: These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect.

PMID: 23094091



The outcome of HIV infection is a delicate balance between genetic characteristics of the virus and of the host. Large genome-wide association studies (GWAS) have scrutinized the entire human genetic code to look for regions that are most closely correlated with outcomes of HIV infection (1). Consistently, the Major Histocompatibility Complex (MHC) region on the short arm of chromosome 6, stands out as being linked to HIV outcomes. This region contains Human Leucocyte Antigen (HLA) genes, and is the most diverse part of the entire human proteome.

An intracellular pathogen like HIV is processed by the host cell machinery, yielding peptide fragments typically 8-11 amino acids in length. These fragments, known as epitopes, are then presented on the surface of the infected cell by HLA class I molecules (see Figure 1). When this HLA-epitope complex is recognized by a T cell receptor on a cytotoxic T lymphocyte (CTL, or CD8+ T cell) a cascade of cytokine release is triggered to kill the infected cell.

Philippa Matthews-jpg

Figure 1: Representation of an HLA   Class I molecule binding an HIV epitope for presentation on the surface of an infected cell.

Images are reconstructed using MacPymol from crystal structures of HLA-B*3501 binding the Nef epitope VPLRPMTY, solved by Smith et al (2). Three alpha domains of the HLA Class I molecule are shown in blue, beta-2 microglobulin in green and the Nef epitope in the peptide binding groove in pink. A,B: structural view showing helices and beta-pleated sheets. C,D: surface view. A,C: side projection. B,D: viewed from above.

To increase the diversity of antigenic fragments that can be presented, each of us carries 6 different HLA genes, two each from loci designated A, B and C. Certain specific HLA genes are linked to successful long-term viraemic suppression (E.g. HLA-B*57).

However, it has also become apparent that combinations of alleles can function in tandem to further improve immune control of viraemia – for example, we have previously shown this is the case for HLA-B*57 when combined with HLA-A*74 (3). Identifying such co-operative pairs of alleles is important in contributing to our understanding of the most successful immune responses – with the ultimate goal in mind of harnessing these responses in a prophylactic or therapeutic vaccine.

In this study, we performed a computational analysis of over 2000 HIV-infected subjects in Southern Africa. We defined disease control by either suppression of HIV set-point viral load, and/or maintenance of CD4+ T cell count in chronic infection. We looked first for single HLA alleles, and then for pairs of alleles that work together to influence disease outcome. These ‘co-operative additive’ effects can predict either good viraemic control (‘benefit’), or loss of disease control (‘hazard’); see Table 1.

One hypothesis to explain the mechanism by which HLA alleles appear to co-operate favourably is that together they present a greater breadth of HIV epitopes. To investigate this, we developed a ‘sharing score’ to quantify epitope coverage mediated by any given pair of alleles. Overall, a larger sharing score for any given pair of alleles (reflecting a greater breadth of epitope coverage) is statistically associated with a stronger co-operative effect. Although this correlation is not a strong one, it does support our hypothesis that breadth of epitope coverage is at least a contributory factor in determining improved disease control.

Overall, this study informs our understanding of which HLA alleles contribute to HIV disease control and demonstrates a tandem effect of certain pairs of HLA alleles in Southern African populations at the epicentre of the HIV pandemic. Finding that beneficial co-operative effects between alleles is associated with breadth of epitope coverage suggests that a successful T cell vaccine should aim to optimize breadth of immune coverage across the HIV proteome.


Table 1: Pairs of alleles with a co-operative additive effect on HIV-1 disease control in Southern Africa. Corrected for multiple comparisons with q<0.05 (false detection rate <5%). Alleles here are resolved to two digits only, with the exception of HLA-B*58 where the high resolution type is known to be significant in determining disease control.

Pairs of alleles associated with   benefit in HIV disease control

Pairs of alleles associated with   hazard in HIV disease control

A*02 and B*81

A*74 and B*57

A*74 and B*81

B*44 and C*04

B*58:01 and B*81

B*58:01 and C*04

B*08 and B*18

B*18 and B*45

B*58:02 and C*16

C*06 and C*16



1 Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1. Science. 2007 Aug 17;317(5840):944-7.

2 Smith KJ, Reid SW, Stuart DI, McMichael AJ, Jones EY, Bell JI. An altered position of the alpha 2 helix of MHC class I is revealed by the crystal structure of HLA-B*3501. Immunity. 1996 Mar;4(3):203-13.

3 Matthews PC, Adland E, Listgarten J, et al. HLA-A*7401-Mediated Control of HIV Viremia Is Independent of Its Linkage Disequilibrium with HLA-B*5703. J Immunol. 2011 Apr 15;186(10):5675-86.


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