Downregulation of major histocompatibility class I on human dendritic cells by HIV Nef impairs antigen presentation to HIV-specific CD8+ T lymphocytes.
The HIV early regulatory Nef protein downregulates surface expression of major histocompatibility class I (MHC I) molecules on various immortalized cell lines and on T lymphocytes. MHC I-restricted presentation induces CD8+ T cell responses, which have a major role in limiting HIV infection. Induction of primary immune responses requires dendritic cells, which are major candidates as the first cells that can internalize the virus and present it to T cells in mucosal contamination. To test the effect of Nef on MHC I-restricted antigen presentation by dendritic cells, we used recombinant vaccinia viruses. Flow cytometric analysis of double labeling for a vaccinia protein and MHC I showed that HIV-1 Lai Nef indeed downregulated MHC I surface expression on dendritic cells. MHC I-restricted presentation to a Nef-specific CD8+ cell clone from an infected patient was decreased in an interferon gamma ELISpot assay. Presentation of a reverse transcriptase epitopic peptide on sorted Nef-infected cells was decreased in a peptide concentration-dependent way, confirming the role of MHC I downregulation in the impairment of the CD8+ cell-specific response. Therefore, Nef downregulates MHC I surface expression on human dendritic cells, impairing presentation to HIV-specific CD8+ cells. This action of Nef probably induces a deleterious delay in the early CD8+ responses during the first days of infection and at the onset of new viral mutants.
Andrieu
M
M
Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM U445, 27 rue du Fbg St-Jacques, 75014 Paris, France.
Chassin
D
D
Desoutter
J F
JF
Bouchaert
I
I
Baillet
M
M
Hanau
D
D
Guillet
J G
JG
Hosmalin
A
A
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015536:Down-Regulation; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D015754:Genes, nef; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D014616:Vaccinia virus; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D054311:nef Gene Products, Human Immunodeficiency Virus