HLA-C and HIV-1: friends or foes?

The major histocompatibility complex (MHC) class I loci are the most polymorphic mammalian genes. The human MHC class I system includes 3 main loci, namely HLA-A, -B and -C, and some non-classical HLA genes such as –E, -F and –G. The HLA-B locus is the most polymorphic, with 1795 proteins known, followed by HLA-A with 1290, and HLA-C with 946 (http://www.ebi.ac.uk/imgt/hla/stats.html webcite). Among the classical MHC class I genes, HLA-C has the least allelic variability [1].MHC class I molecules consist of a 45？kDa heavy, α-chain (divided in 3 subdomains, α1, α2 and α3) 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]. MHC class I assembly occurs in the lumen of the endoplasmic reticulum (ER) with the help of molecular chaperons like calreticulin, ERp57 and tapasin [3]. After leaving the ER the trimeric complexes egress through the Golgi complex to the plasma membrane. At the plasma membrane they can interact with two main types of ligands: the T cell receptor (TCR) of CD8+ T cells and natural killer cells (NK) receptors including immunoglobulin receptors (KIRs), leukocyte immunoglobulin receptors (LILRs) [4,5] and NKG2A/C [6].It is generally agreed that HLA-C is surface-expressed at levels much lower (sometimes said to be ten-fold lower) than HLA-A and HLA-B [7] despite similar levels of transcription and translation [8]. Several authors provided evidence for transcriptional, post-transcriptional, as well as post-translational impairments (reviewed in [9]). Due to such considerable redundancy in the mechanisms accounting for low HLA-C expression, different HLA-C alleles may be affected to various degrees in different cell types or biological conditions. A post-translational biosynthetic bottleneck appears nevertheless to be common, in that it causes the backward accumulation of chaperone-associated and deeply unfolded HLA-C heavy chain confor