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

Hugues Fausther-Bovendo, Nathalie Sol-Foulon, Daniel Candotti, Henri Agut, Olivier Schwartz, Patrice Debré, Vincent Vieillard

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1077-1087
Number of pages11
Issue number9
StatePublished - Jun 1 2009
Externally publishedYes


  • Cytotoxicity
  • HIV escape
  • HIV-1 Nef
  • NKp44 ligand

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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