11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retrovir Opportunistic Infect 2004 Feb 8-11; 11:(abstract no. 17)

J Nattermann¹, H D Nischalke¹, V Hofmeister², B Kupfer¹, G Ahlenstiel¹, G Feldmann¹, J Rockstroh¹, E Weiß², T Sauerbruch¹, U Spengler¹, and BMBF, Kompetenznetz HIV/AIDS
¹Univ. of Bonn, Germany; ¹Univ. of Bonn, Germany; and ²Ludwig-Maximilians-Univ., Munich, Germany

BACKGROUND: Down-regulation of classical major histocompatibility complex (MHC) class I molecules in HIV infection protects the virus from MHC I-restricted cytotoxic T-lymphocytes, but may expose HIV-infected target cells to attack by natural killer. However, HIV-infected lymphocytes are resistant to lysis by NK cells despite reduced MHC I expression. Of note, HIV down-regulates HLA-A and -B, but not HLA-E, an important regulator of NK cell activity. Thus, we studied the role of HLA-E in protection of HIV-infected cells against NK cells.

METHODS: We enrolled in our study 15 HIV-infected patients and 10 healthy HIV-negative subjects. Phytohemagglutinin-treated lymphocytes from HIV-negative donors were infected in vitro with HIV-1. Expression of surface molecules was measured by flow cytometry using the HLA-E-specific monoclonal antibody 3D12 and an HLA-A, -B, -C-specific antibody. HLA-E and TAP mRNA levels were determined by real-time PCR. A chromium-51 release assay was performed following standard protocols.

RESULTS: We found a significantly increased percentage of HLA-E-positive CD4⁺ (2,92%±1.59 vs 0.59%±0.35; p=0.002) and CD8⁺ cells (1.83%±1.67% vs. 0.43%±0.13%, p<0.002) in HIV-RNA positive patients as compared to uninfected subjects. Furthermore, in vitro infection of lymphocytes with HIV-1 resulted in marked up-regulation of HLA-E expression leading to reduced susceptibility of HIV-infected cells to NK cell lysis. Up-regulation of HLA-E expression was neither due to HIV-mediated induction of HLA-E mRNA nor due to up-regulation of TAP1 expression as proven by rt PCR. Using HLA-E-transfected K-562 cells we identified the well-known HIV T-cell epitope p24 aa14-22 as a ligand for HLA-E that stabilizes surface expression of HLA-E and thus inhibits NK cell cytotoxicity. Blocking experiments with monoclonal antibodies specific for NKG2A and HLA-E confirmed that this inhibitory effect of HIV p24 aa14-21 on NK cells was due to interactions of the inhibitory NK cell receptor complex CD94/NKG2A with HLA-E.

CONCLUSIONS: In conclusion, these results propose HIV-mediated up-regulation of HLA-E expression as an efficient evasion strategy targeting the antiviral activities of NK cells and allowing the virus to establish itself as a chronic infection.

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Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.