title: Antibodies and lentiviruses that specifically recognize a T cell epitope derived from HIV-1 Nef protein and presented by HLA-C.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Herschhorn
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
authors.forename: Amnon
authors.initials: A
authors.lastname: Hizi
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D017951:Antigen Presentation / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015483:HIV Antibodies / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D017958:Lentiviruses, Primate / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D015483:HIV Antibodies; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1