Human Leukocyte Antigen (HLA) and Immune Regulation: How Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections?

Abstract

The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the major histocompatibility complex in viral pathogenesis in particular human immunodeficiency virus (HIV) and hepatitis C virus (HCV), is very well documented. We, recently, added a novel insight into the field by identifying the molecular mechanism associated with the protective role of human leukocyte antigen (HLA)-B27/B57 CD8⁺ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA alleles, including class Ia (HLA-A, -B, -C), class Ib (HLA-E, -F, -G, -H), and class II (HLA-DR, -DQ, -DM, and -DP) in immune regulation and viral pathogenesis (e.g., HIV and HCV). To our knowledge, this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.

Keywords: classical human leukocyte antigens; hepatitis C virus and immune regulation; human immunodeficiency virus; human leukocyte antigen; major histocompatibility complex; non-classical human leukocyte antigens.

Figure 1

Simplified diagram of the position and organization of human leukocyte antigen (HLA) genes on human chromosome 6. HLA-class I encompasses “classical” HLA-Ia and “non-classical” HLA-Ib loci, which are differentiated by blue and pink, respectively. HLA-class II are encoded by various HLA-II loci labeled by red. Unlike HLA-class I and II, the HLA-class III region does not encode HLAs. Instead, this densely packed region encodes for various inflammatory molecules, complement, and heat shock proteins. Telomere, ter; p-arm, short arm; q-arm, long arm; Centromere, cen.

Figure 2

Human leukocyte antigen (HLA)-I antigen-processing and presentation pathway. (A) This model depicting how a pathogen (e.g., human immunodeficiency virus) is taken up and processed into small peptides (8–16aa) before binding to HLA-I molecule. (B) HLA-I is assembled in endoplasmic reticulum (ER) and consists of heavy chain and β-2 microglobulin (β2M). Proteins and antigen are degraded/processed by cytosolic and nuclear proteasomes resulting in short peptides called epitopes. Epitopes are translocated into the ER via transporter associated with antigen presentation (TAP). These peptides may require additional trimming in the ER prior to binding to HLA-I molecules. Eventually, epitope:HLA complex will be transported via the Golgi and presented on the cell surface of CD8⁺ T cell. (C) Recognition of the epitope:HLA-I complex via T cell receptor (TCR) activates cytotoxic T cell (CTL) that releases perforin and granzyme B (GzmB) to eliminate the infected cell.

Figure 3

Model depicting differential regulation by CD8⁺ T cells restricted with different human leukocyte antigen (HLA) alleles. HLA-B27 and/or B57-restricted CD8⁺ T cell do not upregulate T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) upon recognition of their cognate epitopes on human immunodeficiency virus (HIV)-infected CD4⁺ T cells, whereas HIV-specific non-B27/B57 such as A03-restricted CD8⁺ T cell upregulate high levels of Tim-3. Regulatory T cells (Tregs) express Galectin 9 (Gal-9) and suppress and kill A03-restricted CD8⁺ T cells due to their high expression of Tim-3 but cannot suppress proliferation of B27-restricted CD8⁺ T cells. Polyfunctional B27-restricted CD8⁺ T cells upregulate high levels of granzyme B (GzmB) and kill not only infected CD4⁺ T cells but also Tregs that they encounter. Therefore, B27-restricted CD8⁺ T cells are capable of keeping HIV replication in control during chronic infection, whereas A03-restricted CD8⁺ T cells lack this ability.

Figure 4

Simplified model of how human leukocyte antigen (HLA)-G mediates its inhibitory functions. (A) Interactions between CD160 on endothelial cells with HLA-G inhibit angiogenesis. (B) ILT2 expression on neutrophils renders them susceptible to inhibition by HLA-G, resulting in a tolerogenic phenotype. (C) The interaction between HLA-G and CD8 on some natural killer (NK) cells triggers FasL-mediated apoptosis, while ILT2:HLA-G impairs NK cell function. (D) ILT2 and immunoglobulin-like transcript 4 (ILT4) present on macrophages interacts with HLA-G, resulting a tolerogenic, immature phenotype with reduced activation markers CD80/86, and major histocompatibility complex (MHC) II. (E) In the presence of HLA-G, mesenchymal stem cells (MSC), and HLA-G, dendritic cells (DCs) that express ILT2 and ILT4 differentiate into DC-10s, which produce high IL-10 and mediate differentiation of Tr1 cells and immaturity of macrophages, and induce widespread immune tolerance. (F) HLA-G:CD8 triggers FasL-mediated apoptosis. KIR2DL4:HLA-G inhibits cytotoxicity, while CD160:HLA-G results in inhibition of proliferation. Upon induction of HLA-G1 on ILT4+ CD4+ T-cells, DC-10 are able to cause their differentiation into Tr1 regulatory cells, which secrete high IL-10 and TGF-β and kill myeloid cells in a Grzm-dependent manner. (G) B-cells express ILT2, it is likely that B-cells are susceptible to HLA-G-mediated suppression. (H) MSC constitutively express HLA-G5 and via HLA-G5 suppress other cells. MSCs also induce CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) via cell-to-cell interaction.

Figure 5

Iron regulation of hepatocytes during normal physiological condition versus conditions of hereditary hemochromatosis (HH) or human immunodeficiency virus (HIV) infection. (A) Under normal physiological iron concentration, transferrin-bound iron is taken up upon binding of saturated transferrin to transferrin receptor 1 (TfR1), which is endocytosed and recycled. Fe(III) (indicated in pink) is oxidized to Fe(II) (indicated in blue) in the endosome and is reduced back to Fe(III). Fe(III) then is stored intracellularly by ferritin. TfR1 and transferrin receptor 2 (TfR2) are in competition for High Fe (HFE). When not associated with HFE, TfR2 is endocytosed, ubiquitinated, and thus degraded by the proteasome. This maintains uptake of iron into the hepatocyte. (B) When too much iron is present in the plasma, HFE interacts with TfR2, preventing its ubiquitination. A multiprotein complex consisting of HFE, GPI-anchor HJV, and TfR2 form on the hepatocyte membrane. HJV is the bone morphogenic protein (BMP) co-receptor, which assists in activating hepcidin gene expression via BMP/SMAD signaling. Hepcidin then limits cellular iron intake by promoting degradation of cellular ferritin, as well as downregulating TfR1 expression. (C) In situations where HFE is absent (i.e., HIV or certain mutations in HFE), TfR2 is unable to interact with HFE and is thus degraded. In states of high physiological iron, TfR2 is unable to mediate hepcidin gene expression. Due to this, cells become iron overloaded labile cell iron (LCI) and non-transferrin-bound labile plasma iron (LPI). These forms of redox-active iron are able to move across cell membranes in a non-regular manner. LCI participates in a Fenton reaction, resulting in overproduction of reactive oxygen species (ROS) that cause lipid peroxidation, protein nitration, and DNA damage. LPI is able to enter other cells irregularly, thus causing even more production of ROS. Eventually, hepcidin production will be triggered due to STAT3 signaling caused by ROS-induced inflammation.