title: HIV-1 CD4-induced (CD4i) gp120 epitope vaccines promote B and T-cell responses that contribute to reduced viral loads in rhesus macaques.
abstract: To target the HIV CD4i envelope epitope, we primed rhesus macaques with replicating Ad-rhFLSC (HIV-1BaLgp120 linked to macaque CD4 D1 and D2), with or without Ad-SIVgag and Ad-SIVnef. Macaques were boosted with rhFLSC protein. Memory T-cells in PBMC, bronchoalveolar lavage and rectal tissue, antibodies with neutralizing and ADCC activity, and Env-specific secretory IgA in rectal secretions were elicited. Although protective neutralizing antibody levels were induced, SHIVSF162P4 acquisition following rectal challenge was not prevented. Rapid declines in serum ADCC activity, Env-specific memory B cells in PBMC and bone marrow, and systemic and mucosal memory T cells were observed immediately post-challenge together with delayed anamnestic responses. Innate immune signaling resulting from persisting Ad replication and the TLR-4 booster adjuvant may have been in conflict and reoriented adaptive immunity. A different adjuvant paired with replicating Ad, or a longer post-prime interval allowing vector clearance before boosting might foster persistent T- and B-cell memory.
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Iskra
authors.initials: I
authors.lastname: Tuero
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Demberg
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Vargas-Inchaustegui
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Musich
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.affiliation: Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Janet
authors.initials: J
authors.lastname: DiPasquale
authors.affiliation: Infectious Diseases Research Institute, Seattle, WA 98102, United States.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: DeVico
authors.affiliation: Profectus BioSciences, Inc., Baltimore, MD 21224, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fouts
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD, United States.
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, MD, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gallo
authors.affiliation: Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: guroffm@mail.nih.gov.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robert-Guroff
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology; D015704:CD4 Antigens / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D012007:Rectum / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology; D019562:Viral Load
chemical_list: D016915:AIDS Vaccines; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: Antibody-dependent cellular cytotoxicity; HIV CD4i epitope; HIV vaccine; Memory B and T cells; Neutralizing antibody; Replication-competent Ad; Rhesus macaque model; Systemic and mucosal adaptive immunity