Figures
Figure 1.
Killer Immunoglobulin-like Receptor Haplotypes. KIR genes are organized into haplotypes A and B. KIR haplotypes A is comprised of four framework genes present in most KIR haplotypes (KIR3DL3 at the centromeric end, KIR3DL2 at the telomeric end and KIR2DL4 and the pseudogene KIR3DP1 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, KIR2DL5A/B and activating KIRs KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 and KIR3DS1 . Most KIR region haplotypes are composed of one of 3 centromeric and one of 3 telomeric KIR motifs that include combinations of KIR genes in linkage disequilibrium with each other, which are usually inherited together. The hotspot in the center between the centromeric and telomeric regions 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; 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 1.
Figure 2.
Antibody independent NK cell anti-HIV activity. (1) In HIV-infected CD4+ cells, Nef downregulates MHC I (i.e. HLA-B*57/27), which are ligands for the inhibitory Killer Immunoglobulin-like Receptor KIR3DL1. (2) Absence of the KIR3DL1 ligands abrogates negative signalling through this receptor changing the balance between negative and positive signals received towards NK cell activation and (3) release of inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IFN-γ and chemokines such as CCL3, CCL4 and CCL5. (4) CCL4 (and CCL3 and CCL5) bind to CCR5, the co-receptor for HIV entry. (5) This blocks the infection of bystander, uninfected CD4+ cells.
Figure 2.
Figure 3.
Comparison of ADCC target cells coated with HIV Envelope gp120 versus Envelope on HIV infected cells. (Left panel ) Gp120-CD4 interactions produce an open Envelope conformation exposing CD4 induced (CD4i) epitopes that are hidden in trimeric closed conformation HIV Envelope. This occurs when target cells are gp120-coated cells or bystander CD4+ cells binding gp120 shed from co-cultured HIV infected cells. This conformation can be recognized by antibodies to CD4i epitopes (shown in blue), some broadly neutralising antibodies (BnAbs, shown in black) but not by many BnAbs (shown in red). In gp120-coated cells, the HIV proteins Env (green), Nef (blue circle) and Vpu (magenta) are absent. The Fc portion of antibodies to the CD4i epitope can bind the activating NK cell receptor, CD16 (2-domain black symbol) to activate NK cells to secrete cytokine, chemokines and lytic granules to kill target cells by ADCC. (Right panel ) Nef and Vpu encoded by HIV infected cells downmodulate CD4 making it unavailable to interact with HIV Envelope. The Envelope is thus presented on the surface of infected cells and is in closed conformation. BnAs shown in red and black recognize this closed Envelope conformation while antibodies to the CD4i epitope shown in blue do not. The Fc portion of Envelope bound antibodies can bind CD16 to activate NK cells to secrete cytokine, chemokines and lytic granules to kill target cells by ADCC.
Figure 3.
Figure 4.
ADNKA and ADCC activity. Nef- and Vpu-mediated downregulation of cell surface CD4 receptor prevents the interaction of CD4 with HIV Envelope, leaving it in a closed trimeric conformation. Antibodies binding this Envelope conformation, shown in red, bind the activating Fc Receptor CD16 on NK cells. ADNKA assesses the secretion of inflammatory cytokines such as TNF-α (red) and IFN-γ (green), and expression of the degranulation marker CD107a (yellow) from NK effector cells whereas ADCC assesses the cytopathic effects of cytolytic granules containing perforin and granzyme B released by NK cells on antibody opsonized target cells.
Figure 4.
Tables
Authors
1 Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, QC, Canada
2 Division of Experimental Medicine, McGill University, Montreal, QC, Canada
3 Infectious Diseases, Immunology and Global Health Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
4 Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
5 Department of Microbiology Infectiology and Immunology, University of Montreal, Montreal, QC, Canada
6 Ph.D., Division of Clinical Immunology, McGill University Health Centre, Montreal, QC, Canada
Untreated HIV infection usually leads to disease progression and development of the acquired immunodeficiency syndrome. A rare subset of people living with HIV control HIV without anti-retroviral therapy. These individuals, known as Elite Controllers (ECs), represent examples of a functional HIV cure. ECs differ from non-controllers is many aspects. Some are infected with defective virus, most have potent CD4 and CD8 virus-specific T cell responses and proviruses in these individuals tend to be inserted into regions with characteristics of deep latency. Natural Killer (NK) cells are innate immune cells that function at the intersection of innate and adaptive immunity. They have the capacity to recognize and respond to HIV-infected cells from the earliest stages in infection. NK cells can be activated through antibody independent and antibody dependent mechanisms to elicit functions that control HIV and kill infected cells. This manuscript will review the role of NK cells in HIV control.