アクティブボード・２０１３年　５月
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研究発表を行った学会；
・Immune Activation in HIV Infection: Basic Mechanisms and Clinical Implications (D2),
　２０１３年　４月　３日〜　８日（Breckenridge, Colorado USA）

タイトル；Differential Nef-mediated down-regulation of HLA-A and B in chronic HIV-1 infection.

発表者；Macdonald Mahiti　氏
　　　（熊本大学　エイズ学研究センター　上野プロジェクト）
Abstract；
HIV-1 Nef down-regulates HLA class I (HLA-I) on the surface of the infected cell, facilitating escape from CTL recognition. HLA-A and B alleles may be differentially susceptible to Nef-mediated down-regulation, due to differential interactions between Nef and locus-specific polymorphic amino acid residues in the HLA-I cytoplasmic tail. However, locus-specific differences in Nef-mediated HLA-I down-regulation abilities have largely been characterized using laboratory-adapted Nef strains. As such, the extent to which naturally-occurring Nef proteins exhibit differential HLA-I down-regulation activities remains unknown. To investigate this, plasma HIV RNA-derived Nef clones were isolated from 45 chronically-infected subjects and inserted into the pNL43 proviral vector. Recombinant viruses were prepared and exposed to the HLA-I deficient cell line 721.221 ectopically expressing either HLA-A*24 or HLA-B*35. Following infection, cell-surface HLA-I expression was evaluated by flow cytometry using the pan HLA-I specific antibody. Although none of the Nef sequences examined harbored amino acid mutations known to disrupt HLA-I down-regulation activity (such as M20A, and P78A), the HLA-I expression levels on the virus-infected cell surface were different dependent on the patient-derived Nef clones, with median [IQR] expression levels of HLA-A*24 and HLA-B*35 of 61.6 [57.4-67.4] % and 53.3 [46.2-57.7] %, respectively, compared to those of uninfected cells as 100%. Thus, the HLA-I down-regulation mediated by patient-derived Nef clones were significantly more susceptible to HLA-A*24 than HLA-B*35 (p<0.001). Taken together, our results support differential susceptibility of HLA-A and HLA-B to Nef-mediated down-regulation in naturally-occurring nef sequences from chronic infection. Results are consistent with a dominant role of HLA-B-restricted CTL responses in modulating viral control during chronic HIV-1 infection.