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Cw13 michigan4/4/2023 ![]() ![]() In addition, HLA-C heavy chain proteins do not efficiently associate with β 2M. ![]() (d) Once on the plasma membrane (PM), the rate of HLA-C internalization and lysosomal degradation is regulated by phosphorylation of serine residue 335. (c) HLA-C is able to bind a limited repertoire of peptides, and molecules accumulating in the ER waiting for peptide loading are eventually targeted for degradation. (b) Once translated, the HLA-C heavy chain does not efficiently associate with β 2-microglobulin (β 2M blue circle) in the endoplasmic reticulum (ER). (a) The presence of a single base pair insertion polymorphism in the 3′-untranslated region (263ins) of HLA-C mRNA (wavy line) results in the creation of a microRNA binding site causing post-transcriptional cleavage or destabilization. HLA-C surface expression is regulated through multiple mechanisms. For reasons that are poorly understood, HLA-C is normally expressed on the cell surface at levels approximately 10-fold less than most HLA-A and HLA-B allotypes. HLA-C plays a dual role in that it can present antigens to CTLs and it can inhibit natural killer (NK) cell (and possibly also CTL) lysis via its interaction with inhibitory receptors. The HLA-C protein is a heterodimer composed of a membrane-bound mature heavy chain and a light chain, β 2-microglobulin (β 2M). 7 HLA-C biology is still under active investigation to define its role in the immune response and the selective pressures that define its diversity (for recent review see ref. There are also functional differences among these molecules that may restrict diversity KIRs recognize all HLA-C allotypes, but only some HLA-A and -B allotypes. ![]() 5 HLA-C is the most recently evolved of the classical MHC-I alleles and is restricted to humans and great apes 4, 6 and fewer alleles of HLA-C have been identified. The HLA-A and -B molecules in particular are highly polymorphic with the greatest variability found within the peptide-binding region, which supports their function in presentation of diverse antigens to cytotoxic T lymphocytes (CTLs). ![]() There is evidence that evolution of the HLA-A, -B and -C loci is driven by pathogen-mediated selection. The MHC-I locus on chromosome 6 in the human genome comprises two groups, the highly polymorphic classical class I molecules (HLA-A, -B and -C)and the conserved non-classical molecules (HLA-E, -F and –G) (reviewed in ref. Insight gained from these studies will shed light on the role of these complex molecules in the innate and adaptive immune responses. 1 – 3 This review will summarize these findings, supporting a role for HLA-C in HIV disease progression. Recently, genome-wide association studies have implicated a role for high HLA-C surface expression in the control of HIV. A subset of MHC-I allotypes are associated with delayed disease progression and effective control of viral replication, most notably HLA-B*5701. MHC-I present viral peptides to CD8 + T cells and serve as ligands for killer cell immunoglobulin-like receptors (KIRs). Major histocompatibility complex class I molecules (MHC-I) are necessary for an effective host immune response to HIV infection. A greater understanding of the immune response to HIV and the mechanisms of viral immune evasion will facilitate this goal as well as further the development of therapeutics to eliminate HIV infection. Addressing this significant global health problem calls for the development of preventative and therapeutic vaccines. Although HAART controls the disease, complete eradication of the virus has yet to be achieved. Currently the only effective treatment for the disease is Highly Active Anti-Retroviral Therapy (HAART). Infection with HIV is a global health problem, with over 2 million AIDS-related deaths per year ( ). ![]()
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