Abstract
Natural killer (NK) cells’ major role in the control of viruses is to eliminate established infected cells. The capacity of NK cells to kill virus-infected cells is dependent on the interactions between ligands on the infected cell and receptors on the NK cell surface. Because of the importance of ligand-receptor interactions in modulating the NK cell cytotoxic response, HIV has developed strategies to regulate various NK cell ligands making the infected cell surprisingly refractory to NK cell lysis. This is perplexing because the HIV-1 accessory protein Vpr induces expression of ligands for the NK cell activating receptor, NKG2D. In addition, the accessory protein Nef removes the inhibitory ligands HLA-A and -B. The reason for the ineffective killing by NK cells despite the strong potential to eliminate infected cells is due to HIV-1 Vpu’s ability to down modulate the co-activation ligand, NTB-A, from the cell surface. Down modulation of NTB-A prevents efficient NK cell degranulation. This review will focus on the mechanisms through which the HIV-1 accessory proteins modulate their respective ligands, and its implication for NK cell killing of HIV-infected cells.
Highlights
Natural killer (NK) cells’ major role in the control of viruses is to eliminate established infected cells
immunoreceptor tyrosine-based activation motifs (ITAMs) containing adaptor molecules include: DAP12, FcεRIγ, and CD3δ [25,49]. These adaptor proteins become phosphorylated by tyrosine kinases such as Syk and ZAP-70 allowing for NK cell cytotoxicity (See Table 1 for list of aNKRs) [50]
In more recent study, deleting negative regulatory factor (Nef) from HIV-1 resulted in surface expression of NKG2D ligands to the same level as wild-type infected cells [99]
Summary
An important first line of defense against viruses involves natural killer (NK) cells. Loose interactions between Ag LewisX and lectin-like receptors such as CD94 and NKG2D may allow for the NK cell to slow down and initiate longer contact with its target [28] This loose adhesion between NK and target cells is soon followed by a stable interaction involving integrins (e.g., lymphocyte function-associated antigen (LFA)-1) on NK cells and the intercellular adhesion molecules (ICAM) family on target cells [29,30]. The cytotoxic granules migrate in the direction of the microtubule-organizing center (MTOC) towards the minus ends of the microtubules found at the MTOC [36] This is followed by actin cytoskeleton rearrangement that recruits activating receptors into lipid rafts. Immunological synapse contains a ―lipid raft‖ domain (shown in black) containing activating receptors This is adjacent to a section of the plasma membrane allowing for the unobstructed release of perforin and granzymes, into the space between the NK cell and target
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