HIV and HLA class I: an evolving relationship

Abstract

Successful vaccine development for infectious diseases has largely been achieved in settings where natural immunity to the pathogen results in clearance in at least some individuals. HIV presents an additional challenge in that natural clearance of infection does not occur, and the correlates of immune protection are still uncertain. However, partial control of viremia and markedly different outcomes of disease are observed in HIV-infected persons. Here, we examine the antiviral mechanisms implicated by one variable that has been consistently associated with extremes of outcome, namely HLA class I alleles, and in particular HLA-B, and examine the mechanisms by which this modulation is likely to occur and the impact of these interactions on evolution of the virus and the host. Studies to date provide evidence for both HLA-dependent and epitope-dependent influences on viral control and viral evolution and have important implications for the continued quest for an effective HIV vaccine.

Figure 1

Defined HLA class I and class II alleles by year from 1968-2012. Graph taken from http://www.ebi.ac.uk/imgt/hla/intro.html, copyright SGE Marsh 07/2012, with permission].

Figure 2

Potential mechanisms of HLA-associated impact on viral control. The HLA class I molecule is a heterodimer consisting of three alpha helices and β-2 microglobulin. The alpha 1 and alpha 2 domains together form the peptide binding groove, which presents viral peptides at the surface of an infected cell, and this complex is in turn recognized by the T cell receptor on CD8⁺ T cells, through interactions with both the TCR and CD8 receptor (shown). The HLA molecule or peptide-HLA complex may also bind KIR and LILR (not shown). The mechanisms by which HLA and its interactions with CD8⁺ T cells, TCR, epitope, and infected cells, as well as HLA-specific mechanisms, have been shown to modulate the efficacy of HIV control are listed in the adjacent table.