title: X4 human immunodeficiency virus type 1 gp120 down-modulates expression and immunogenicity of codelivered antigens.
abstract: In order to increase the immune breadth of human immunodeficiency virus (HIV) vaccines, strategies such as immunization with several HIV antigens or centralized immunogens have been examined. HIV-1 gp120 protein is a major immunogen of HIV and has been routinely considered for inclusion in both present and future AIDS vaccines. However, recent studies proposed that gp120 interferes with the generation of immune response to codelivered antigens. Here, we investigate whether coimmunization with plasmid-encoded gp120 alters the immune response to other coadministered plasmid encoded antigens such as luciferase or ovalbumin in a mouse model. We found that the presence of gp120 leads to a significant reduction in the expression level of the codelivered antigen in vivo. Antigen presentation by antigen-presenting cells was also reduced and resulted in the induction of weak antigen-specific cellular and humoral immune responses. Importantly, gp120-mediated immune interference was observed after administration of the plasmids at the same or at distinct locations. To characterize the region in gp120 mediating these effects, we used plasmid constructs encoding gp120 that lacks the V1V2 loops (DeltaV1V2) or the V3 loop (DeltaV3). After immunization, the DeltaV1V2, but not the DeltaV3 construct, was able to reduce antigen expression, antigen presentation, and subsequently the immunogenicity of the codelivered antigen. The V3 loop dependence of this phenomenon seems to be limited to V3 loops known to interact with the CXCR4 molecule but not with CCR5. Our study presents a novel mechanism by which HIV-1 gp120 interferes with the immune response against coadministered antigen in a polyvalent vaccine preparation.
authors.affiliation: Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, P.O. Box 122722, Jerusalem 91120, Israel. avihaih@ekmd.huji.ac.il
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: Maytal
authors.initials: M
authors.lastname: Bivas-Benita
authors.forename: Andre
authors.initials: A
authors.lastname: Plair
authors.forename: Alex
authors.initials: A
authors.lastname: Cheng
authors.forename: Mazal
authors.initials: M
authors.lastname: Elnekave
authors.forename: Elda
authors.initials: E
authors.lastname: Righi
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kashiwagi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Panas
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Karina
authors.initials: K
authors.lastname: Furmanov
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Mark C
authors.initials: MC
authors.lastname: Poznansky
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis; D005260:Female; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; C514793:gp120 protein, Human immunodeficiency virus 1; D010047:Ovalbumin
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