RT Journal Article SR Electronic(1) A1 Cerboni, Cristina A1 Neri, Francesca A1 Casartelli, Nicoletta A1 Zingoni, Alessandra A1 Cosman, David A1 Rossi, Paolo A1 Santoni, Angela A1 Doria, MargheritaYR 2007 T1 Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity JF Journal of General Virology, VO 88 IS 1 SP 242 OP 250 DO https://doi.org/10.1099/vir.0.82125-0 PB Microbiology Society, SN 1465-2099, AB Natural killer (NK) cells are a major component of the host innate immune defence against various pathogens. Several viruses, including Human immunodeficiency virus 1 (HIV-1), have developed strategies to evade the NK-cell response. This study was designed to evaluate whether HIV-1 could interfere with the expression of NK cell-activating ligands, specifically the human leukocyte antigen (HLA)-I-like MICA and ULBP molecules that bind NKG2D, an activating receptor expressed by all NK cells. Results show that the HIV-1 Nef protein downmodulates cell-surface expression of MICA, ULBP1 and ULBP2, with a stronger effect on the latter molecule. The activity on MICA and ULBP2 is well conserved in Nef protein variants derived from HIV-1-infected patients. In HIV-1-infected cells, cell-surface expression of NKG2D ligands increased to a higher extent with a Nef-deficient virus compared with wild-type virus. Mutational analysis of Nef showed that NKG2D ligand downmodulation has structural requirements that differ from those of other reported Nef activities, including HLA-I downmodulation. Finally, data demonstrate that Nef expression has functional consequences on NK-cell recognition, causing a decreased susceptibility to NK cell-mediated lysis. These findings provide a novel insight into the mechanisms evolved by HIV-1 to escape from the NK-cell response., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.82125-0