Illustrations
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.
Tableaux
Auteurs
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
Contribution des cellules tueuses naturelles chez les sujets contrôleurs d’élite du VIH. En l’absence de traitement antirétroviral, l’infection par le VIH progresse normalement vers le syndrome d’immunodéficience acquise. Une minorité de sujets infectés par le VIH sont toutefois capables de contrôler la réplication virale en l’absence de traitement. Ces patients appelés sujets contrôleurs d’élite (EC pour elite controllers) représentent un exemple de guérison fonctionnelle de l’infection par le VIH. Certains EC sont infectés par des virus défectifs, alors que d’autres ont des provirus intégrés dans des zones non transcrites de la chromatine. Cependant, la plupart des EC se distinguent des sujets non-contrôleurs parce qu’ils développent de fortes réponses T CD4 et CD8 spécifiques au VIH. Les cellules tueuses naturelles (NK pour Natural Killer) sont des cellules du système immunitaire inné qui fonctionnent à l’interface entre l’immunité innée et l’immunité acquise. Les cellules NK sont capables de reconnaître et de répondre à des cellules infectées dès les stades précoces de l’infection. Les cellules NK peuvent être activées de fac¸on indépendante et dépendante des anticorps afin d’exercer des fonctions antivirales et éliminer les cellules infectées. Ce manuscrit discutera du rôle des cellules NK dans le contrôle de l’infection par le VIH.