Abstract
The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins.
Highlights
The major histocompatibility complex (MHC) class I loci are the most polymorphic mammalian genes
MHC class I molecules consist of a 45 kDa heavy, α-chain non-covalently associated with a light β chain, the β2-microglobulin (β2m), and a short (8-11mer) peptide antigen derived from the degradation of intracellular proteins [2]
C*02, C*05, C*06, C*08, C*12, C*15 and C*16, containing a disrupted binding site, are highly expressed. These findings offer a rational explanation of different HLA-C expression levels initially reported to be associated with the −35 kb single nucleotide polymorphism (SNP) and are consistent with previous genetic association studies which identified C*04 and C*07 as risk alleles [34,35,36] and C*02 and C*12 [52] as protective alleles [53]
Summary
The major histocompatibility complex (MHC) class I loci are the most polymorphic mammalian genes. The KIR2DL2-HLA-C1 compound was shown to drive viral evolution in vivo since KIR2DL2-associated HIV-1 sequence polymorphisms were shown to enhance the binding of inhibitory KIRs to HIV-1 infected CD4+ T cells and to reduce anti-viral activity of KIR-positive NK cells thereby enabling HIV-1 to escape the potential protective role of KIR [77] Another KIR/HLA compound genotype relevant to HIV1 control is KIR3DL1 and KIR3DS1, which encode receptors for molecules of the Bw4 subfamily of HLA-B alleles. The study showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present, as does an increase in KIR3DL1 count in the presence of KIR3DS1 and the appropriate ligands for both receptors, suggesting that the relative amounts of activator and inhibitory KIR regulate the expansion of antiviral NK cells [23] It should be considered, that inhibition by HLAB allotypes is less common compared to inhibition by HLA-C since it has only been shown for the Bw4 subfamily. This property may confer to HLA-C open conformers a selective propensity for associating with viral proteins
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