HIV escape from natural killer cytotoxicity: nef inhibits NKp44L expression on CD4+ T cells.
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.


METHODS
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.


CONCLUSIONS
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.
INSERM UMR945, Hôpital Pitié-Salpêtrière, Paris, France.
Hugues
H
Fausther-Bovendo
Nathalie
N
Sol-Foulon
Daniel
D
Candotti
Henri
H
Agut
Olivier
O
Schwartz
Patrice
P
Debré
Vincent
V
Vieillard
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000037:antagonists & inhibitors; D014616:Vaccinia virus / Q000276:immunology; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
C112837:NCR2 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2; D054311:nef Gene Products, Human Immunodeficiency Virus