NK Cells in Protection from HIV Infection

Abstract

Some people, known as HIV-exposed seronegative (HESN) individuals, remain uninfected despite high levels of exposure to HIV. Understanding the mechanisms underlying their apparent resistance to HIV infection may inform strategies designed to protect against HIV infection. Natural Killer (NK) cells are innate immune cells whose activation state depends on the integration of activating and inhibitory signals arising from cell surface receptors interacting with their ligands on neighboring cells. Inhibitory NK cell receptors use a subset of major histocompatibility (MHC) class I antigens as ligands. This interaction educates NK cells, priming them to respond to cells with reduced MHC class I antigen expression levels as occurs on HIV-infected cells. NK cells can interact with both autologous HIV-infected cells and allogeneic cells bearing MHC antigens seen as non self by educated NK cells. NK cells are rapidly activated upon interacting with HIV-infected or allogenic cells to elicit anti-viral activity that blocks HIV spread to new target cells, suppresses HIV replication, and kills HIV-infected cells before HIV reservoirs can be seeded and infection can be established. In this manuscript, we will review the epidemiological and functional evidence for a role for NK cells in protection from HIV infection.

Keywords: HIV; HIV-exposed seronegative; HLA; HLA-B*57; killer immunoglobulin-like receptors; natural killer cells.

Figure 1

Killer Immunoglobulin-like Receptor Haplotypes. KIR genes are organized into haplotypes A and B. KIR genes shown in the bottom row are designated without “KIR” before their names. The different colors are used to identify different genes. Haplotype A is comprised of four framework genes present in most KIR haplotypes (KIR3DL3 at the centromeric end, KIR3DL2 at the telomeric end and the pseudogene KIR3DP1 and KIR2DL4 in the middle) plus genes encoding inhibitory KIRs KIR2DL1, KIR2DL3, KIR3DL1, activating KIR KIR2DS4 and pseudogene KIR2DP1. The more diverse group B haplotypes include the framework genes with various combinations of genes encoding inhibitory KIRs KIR2DL2 and KIR2DL5A/B and activating KIRs KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, and KIR3DS1. More than 90% of the 68 haplotypes that have been sequenced to date using full haplotype multiple-sequence alignments are composed of one of four centromeric and one of three telomeric KIR motifs that include combinations of KIR genes in linkage disequilibrium with each other, which are usually inherited together. The intergenic region between KIR3DP1 and KIR2DL4 is a hotspot between the centromeric and telomeric regions, which allows for frequent recombination between the two regions. The centromeric region is delimited by the framework genes KIR3DL3 and KIR3DP1, while the telomeric region is delimited by framework genes KIR2DL4 and KIR3DL2. KIR2DP1 and KIR2DP1 are pseudogenes. cA01 = genes in the centromeric region of KIR haplotype A 1; cB01 = genes in the centromeric region of KIR haplotype B 1; cB02 = genes in the centromeric region of KIR haplotype B 2; cB03 = genes in the centromeric region of KIR haplotype B 3; tA01 = genes in the telomeric region of KIR haplotype A 1; tA02 = genes in the telomeric region of KIR haplotype A 2; tB01 = genes in the telomeric region of KIR haplotype B 1.

Figure 2

Target recognition, tolerance, and missing-self recognition. NK cells recognize and kill their targets through the integration of signals received from inhibitory and activating receptors. They can discriminate between healthy cells (tolerance) and eliminate transformed or virally infected targets (killing). As shown to the left of the vertical dotted line that separates the figure into two parts, NK-cell tolerance depends on the interaction of several major histocompatibility complex (MHC) class I ligands (either classical, HLA-A, -B, or -C, or nonclassical, HLA-E) expressed by heathy cells with their inhibitory KIR or NKG2A receptors with minimal activation signals. Shown here as an example is expression of the MHC class I antigen HLA-B*57 on healthy cells engaging the inhibitory receptor KIR3DL1 on NK cells, transducing inhibitory signals that maintain NK cells in a resting state. HIV uninfected cells express few ligands for activating receptors. On the right, HIV-infected cells downmodulated HLA, abrogating inhibitory signals through KIR3DL1. HIV-infected cells also upregulate ligands for activating NK cell receptors. Loss of inhibitory signaling (as indicated by the “+” symbol over the ligand for inhibitory KIR3DL1) and gain of activating signaling activates NK cells to release cytokines and cytotoxic mediators, which kill HIV-infected cells. Dark green bar on the NK cell = activating NK cell receptor; light green bar on HIV infected cell (right panel) = ligand for an activating receptor (this bar in missing on HIV uninfected cells in left hand panel as indicated by the “+” symbol); blue three domain structure on the NK cell = inhibitory KIR3DL1 receptor; grey 4 domain structure on HIV uninfected cells (left-hand panel) = HLA-B*57, a ligand for inhibitory receptor KIR3DL1 (this HLA antigen is missing on the HIV infected cell in left hand panel as indicated by the “+” symbol); purple dots = cytokines and cytotoxic mediators.

Figure 3

NK cell responses to allogenic cells. Shown in the top middle is an NK cell from an HIV uninfected person expressing the inhibitory receptor/ligand combination KIR2DL1/HLA-C2. The interaction of KIR2DL1 with HLA-C2 during development educates these NK cells. When educated KIR2DL1⁺ NK cells in a recipient partner encounter incoming HIV-infected CD4 cells from a transmitting partner who is HLA-C2⁺ (bottom left-hand cell, matched combination), the interaction of HLA-C2 on infected cells with the KIR2DL1 inhibitory receptor on recipient partner NK cells inhibits NK cell activation despite HIV-infected cells having ligands for activating receptors on NK cells. In this scenario, cytolysis of the HIV-infected cells is inhibited, increasing the chance of HIV transmission. On the right, educated KIR2DL1⁺ NK cells in a recipient partner encounter incoming HIV-infected CD4 cells from a transmitting partner who is HLA-C1⁺ (bottom right-hand cell, unmatched combination). Absence of inhibitory signaling through KIR2DL1 together with the presence of activating signals from activating receptors interacting with their ligands on HIV-infected cells activates NK cells. Activated NK cells release cytokines and cytotoxic mediators, which suppress and/or kill incoming HIV-infected cells and reduce the chance of HIV transmission. Light green bar = ligand for an activating receptor; dark green bar on the NK cell = activating NK cell receptor; purple 2 domain structure on the NK cell = inhibitory NK cell receptor KIR2DL2; light pink 4 domain structure on the HIV infected cell (left) = HLA-C2, a ligand for inhibitory receptor KIR2DL1; blue 4 domain structure on the HIV infected cell (right) = HLA-C1, unable to bind inhibitory receptor KIR2DL1; purple dots = cytokines and cytotoxic mediators; “+” symbol between KIR2DL1 and HLA-C1 on the right indicated the absence of an interaction between this receptor and ligand pair.