TY - JOUR
T1 - Antibodies and lentiviruses that specifically recognize a T cell epitope derived from HIV-1 Nef protein and presented by HLA-C
AU - Herschhorn, Alon
AU - Marasco, Wayne A.
AU - Hizi, Amnon
PY - 2010/12/15
Y1 - 2010/12/15
N2 - HIV selectively downregulates HLA-A and-B from the surfaces of infected cells to avoid detection by the immune system. In contrast, the HLA-C molecules are highly resistant to this downregulation. High expression level of HLA-C on the cell surface, which correlates with a single nucleotide polymorphism, is also associated with lower viral loads and slower progression to AIDS. These findings strongly suggest that HIV-1-derived peptides are efficiently presented by HLA-C and trigger the elimination of infected cells. Accordingly, the ability to detect these HLA-C-peptide complexes may be used for therapeutic targeting of HIV-1-infected cells and for measuring effective presentation of vaccine candidates after immunization with HIV-1-related proteins or genes. However, low level of HLA-C expression on the cell surface has impeded the development of such complex-recognizing reagents. In this study, we describe the development of a high-affinity human Ab that specifically interacts, at low pM concentrations, with a conserved viral T cell epitope derived from HIV-1 Nef protein and presented by HLA-C. The human Ab selectively detects this complex on different cells and does not interact with a control complex that differed only in the presented peptide. Engineering lentiviruses to display this Ab endowed them with the same specificity as the Ab, whereas coexpressing the Ab and Fas ligand enables the lentiviruses to kill specifically Nef-presenting cells. Abs and pseudoviruses with such specificity are likely to be highly valuable as building blocks for specific targeting and killing of HIV-1-infected cells.
AB - HIV selectively downregulates HLA-A and-B from the surfaces of infected cells to avoid detection by the immune system. In contrast, the HLA-C molecules are highly resistant to this downregulation. High expression level of HLA-C on the cell surface, which correlates with a single nucleotide polymorphism, is also associated with lower viral loads and slower progression to AIDS. These findings strongly suggest that HIV-1-derived peptides are efficiently presented by HLA-C and trigger the elimination of infected cells. Accordingly, the ability to detect these HLA-C-peptide complexes may be used for therapeutic targeting of HIV-1-infected cells and for measuring effective presentation of vaccine candidates after immunization with HIV-1-related proteins or genes. However, low level of HLA-C expression on the cell surface has impeded the development of such complex-recognizing reagents. In this study, we describe the development of a high-affinity human Ab that specifically interacts, at low pM concentrations, with a conserved viral T cell epitope derived from HIV-1 Nef protein and presented by HLA-C. The human Ab selectively detects this complex on different cells and does not interact with a control complex that differed only in the presented peptide. Engineering lentiviruses to display this Ab endowed them with the same specificity as the Ab, whereas coexpressing the Ab and Fas ligand enables the lentiviruses to kill specifically Nef-presenting cells. Abs and pseudoviruses with such specificity are likely to be highly valuable as building blocks for specific targeting and killing of HIV-1-infected cells.
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U2 - 10.4049/jimmunol.1001561
DO - 10.4049/jimmunol.1001561
M3 - Article
C2 - 21076072
AN - SCOPUS:78650650781
SN - 0022-1767
VL - 185
SP - 7623
EP - 7632
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -