Natural killer (NK) cell degranulation in response to virus-infected cells is triggered by interactions between invariant NK cell surface receptors and their ligands on target cells. Although HIV-1 Vpr induces expression of ligands for NK cell activation receptor, NKG2D, on infected cells, this is not sufficient to promote lytic granule release. We show that triggering the NK cell coactivation receptor NK-T- and -B cell antigen (NTB-A) alongside NKG2D promotes NK cell degranulation. Normally, NK cell surface NTB-A binds to NTB-A on CD4+ T cells. However, HIV-1 Vpu downmodulates NTB-A on infected T cells. Vpu associates with NTB-A through its transmembrane region without promoting NTB-A degradation. Cells infected with HIV-1 Vpu mutant elicited at least 50% more NK cells to degranulate than wild-type virus. Moreover, NK cells have a higher capacity to lyse HIV-infected cells with a mutant Vpu. Thus, Vpu downmodulation of NTB-A protects the infected cell from lysis by NK cells.
Bibliographical noteFunding Information:
The authors would like to thank Dr. Alessandro Moretta, University of Genoa, Genoa, Italy, for providing us with the ON56 clone of anti-NTB-A antibody. This work was supported by grants from NIH/NIAID: AI65361 and AI81684 for E.B. and AI49057 and AI81684 for V.P.