TY - JOUR
T1 - HIV escape from natural killer cytotoxicity
T2 - Nef inhibits NKp44L expression on CD4+ T cells
AU - Fausther-Bovendo, Hugues
AU - Sol-Foulon, Nathalie
AU - Candotti, Daniel
AU - Agut, Henri
AU - Schwartz, Olivier
AU - Debré, Patrice
AU - Vieillard, Vincent
PY - 2009/6/1
Y1 - 2009/6/1
N2 - OBJECTIVE:: HIV infection induces a progressive depletion of CD4 T cells. We showed that NKp44L, a cellular ligand for an activating natural killer (NK) receptor, is expressed on CD4 T cells during HIV infection and is correlated with both CD4 cell depletion and increase in viral load. NKp44LCD4 T cells are highly sensitive to the NK lysis activity. In contrast, HIV-infected CD4 T cells are resistant to NK killing, suggesting that HIV-1 developed strategies to avoid detection by the host cell immunity. DESIGN:: To assess whether viral protein can affect NKp44L expression, using Nef-deficient virus as well as a panel of recombinant vaccinia viruses expressing all HIV-1 viral proteins was tested. The involvement of Nef in the downmodulation of NKp44L was determined using defined mutants of Nef. Functional consequences of Nef on NK-cell recognition were evaluated by either 51Cr-release assays and degranulation assays in presence of anti-NKp44L mAb. RESULTS:: We observed that during HIV-1 infection, noninfected CD4 T cells exclusively expressed NKp44L, and demonstrate that Nef mediates NKp44L intracellular retention in HIV-infected cells. This has functional consequences on HIV-infected CD4 T cells recognition by NK cells, causing a decreased susceptibility to NK cytotoxicity. Furthermore, experiments in presence of neutralizing NKp44L mAb revealed that Nef inhibitory effect on NK cytotoxicity mainly depends on the NKp44L pathway. CONCLUSION:: This novel escape mechanism could explain the resistance of HIV-infected cells to NK lysis and as a result play a key role in maintaining the HIV reservoir by avoiding recognition by NK cells.
AB - OBJECTIVE:: HIV infection induces a progressive depletion of CD4 T cells. We showed that NKp44L, a cellular ligand for an activating natural killer (NK) receptor, is expressed on CD4 T cells during HIV infection and is correlated with both CD4 cell depletion and increase in viral load. NKp44LCD4 T cells are highly sensitive to the NK lysis activity. In contrast, HIV-infected CD4 T cells are resistant to NK killing, suggesting that HIV-1 developed strategies to avoid detection by the host cell immunity. DESIGN:: To assess whether viral protein can affect NKp44L expression, using Nef-deficient virus as well as a panel of recombinant vaccinia viruses expressing all HIV-1 viral proteins was tested. The involvement of Nef in the downmodulation of NKp44L was determined using defined mutants of Nef. Functional consequences of Nef on NK-cell recognition were evaluated by either 51Cr-release assays and degranulation assays in presence of anti-NKp44L mAb. RESULTS:: We observed that during HIV-1 infection, noninfected CD4 T cells exclusively expressed NKp44L, and demonstrate that Nef mediates NKp44L intracellular retention in HIV-infected cells. This has functional consequences on HIV-infected CD4 T cells recognition by NK cells, causing a decreased susceptibility to NK cytotoxicity. Furthermore, experiments in presence of neutralizing NKp44L mAb revealed that Nef inhibitory effect on NK cytotoxicity mainly depends on the NKp44L pathway. CONCLUSION:: This novel escape mechanism could explain the resistance of HIV-infected cells to NK lysis and as a result play a key role in maintaining the HIV reservoir by avoiding recognition by NK cells.
KW - Cytotoxicity
KW - HIV escape
KW - HIV-1 Nef
KW - NKp44 ligand
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U2 - 10.1097/QAD.0b013e32832cb26b
DO - 10.1097/QAD.0b013e32832cb26b
M3 - Article
C2 - 19424050
AN - SCOPUS:67651102980
SN - 0269-9370
VL - 23
SP - 1077
EP - 1087
JO - AIDS
JF - AIDS
IS - 9
ER -