title: Potent cross-reactive immune response against the wild-type and drug-resistant forms of HIV reverse transcriptase after the chimeric gene immunization.
abstract: HIV reverse transcriptase (RT) can be considered as a target and an instrument of immunotherapy aimed at limiting the emergence and spread of drug-resistant HIV. The chimeric genes coding for the wild-type and multi-drug-resistant RT (RT1.14) fused to lysosome-associated membrane protein 1 (LAMP-1) were injected intramuscularly into BALB/c mice. The immune response was assessed by ELISpot, cytokine ELISA intracellular IFN-gamma staining, and antibody ELISA. The genes for RT- and RT1.14-LAMP fusions (RT-LAMP and RT1.14-LAMP) were immunogenic generating a mixed Th1/Th2-profile of immune response, while the wild-type RT gene induced only weak immune response. Specific secretion of Th1-cytokines increased with increasing level of RT modification: RT<RT1.14 approximately RT-LAMP<RT1.14-LAMP. LAMP gene fusions generated a cross-reactive T-cell response against epitopes harboring drug-resistance mutations and their wild-type variants. Gene immunization induced specific IgG (10(3)), and transient serum IgA (10(2)). Low immunogenicity of the parental RT may be explained by tolerance to the enzyme that is a common endogenous retroviral antigen. Potent immune recognition of RT after immunization with chimeric RT genes indicates that this tolerance could be overcome. Immunization with mutant HIV genes may represent an immunotherapeutical supplement to antiretroviral treatment preventing the emergence of drug resistance.
authors.affiliation: Swedish Institute for Infectious Disease Control, Nobelsvägen 18, 17182 Stockholm, Sweden. estarodubova@gmail.com
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Starodubova
authors.forename: Andreas
authors.initials: A
authors.lastname: Boberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Ivanov
authors.forename: Oleg
authors.initials: O
authors.lastname: Latyshev
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrakova
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kuzmenko
authors.forename: Marina
authors.initials: M
authors.lastname: Litvina
authors.forename: Alexander
authors.initials: A
authors.lastname: Chernousov
authors.forename: Sergey
authors.initials: S
authors.lastname: Kochetkov
authors.forename: Vadim
authors.initials: V
authors.lastname: Karpov
authors.forename: Britta
authors.initials: B
authors.lastname: Wahren
authors.forename: Maria G
authors.initials: MG
authors.lastname: Isaguliants
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation; D003429:Cross Reactions; D016207:Cytokines / Q000276:immunology; D024882:Drug Resistance, Viral / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000201:enzymology / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007111:Immunity, Cellular; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008213:Lymphocyte Activation; D051907:Lysosomal Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D016915:AIDS Vaccines; D016207:Cytokines; D015483:HIV Antibodies; D054303:HIV Reverse Transcriptase; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D051907:Lysosomal Membrane Proteins; D019444:Vaccines, DNA; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1