title: Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection.
abstract: A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.
authors: Profectus Biosciences, Inc., Baltimore, MD 21224; rgallo@ihv.umaryland.edu fouts@profectusbiosciences.net.
authors: Timothy R
authors: TR
authors: Fouts
authors: Profectus Biosciences, Inc., Baltimore, MD 21224;
authors: Kenneth
authors: K
authors: Bagley
authors: Profectus Biosciences, Inc., Baltimore, MD 21224;
authors: Ilia J
authors: IJ
authors: Prado
authors: Profectus Biosciences, Inc., Baltimore, MD 21224;
authors: Kathryn L
authors: KL
authors: Bobb
authors: Profectus Biosciences, Inc., Baltimore, MD 21224;
authors: Jennifer A
authors: JA
authors: Schwartz
authors: Profectus Biosciences, Inc., Tarrytown, NY 10591;
authors: Rong
authors: R
authors: Xu
authors: Center for Infectious Disease and Immunology Research Institute, Rochester General Hospital, Rochester, NY 14621;
authors: Robert J
authors: RJ
authors: Zagursky
authors: Profectus Biosciences, Inc., Tarrytown, NY 10591;
authors: Michael A
authors: MA
authors: Egan
authors: Profectus Biosciences, Inc., Tarrytown, NY 10591;
authors: John H
authors: JH
authors: Eldridge
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710;
authors: Celia C
authors: CC
authors: LaBranche
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710;
authors: David C
authors: DC
authors: Montefiori
authors: INSERM U976, F-75475 Paris, France;
authors: Hélène
authors: H
authors: Le Buanec
authors: NEOVACS S.A., 75014 Paris, France;
authors: Daniel
authors: D
authors: Zagury
authors: Advanced Bioscience Laboratories, Rockville, MD 20850;
authors: Ranajit
authors: R
authors: Pal
authors: Human Retrovirus Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201;
authors: George N
authors: GN
authors: Pavlakis
authors: Human Retrovirus Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201;
authors: Barbara K
authors: BK
authors: Felber
authors: Virus Tumor Biology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-5065; and.
authors: Genoveffa
authors: G
authors: Franchini
authors: Virus Tumor Biology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-5065; and.
authors: Shari
authors: S
authors: Gordon
authors: Virus Tumor Biology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-5065; and.
authors: Monica
authors: M
authors: Vaccari
authors: Institute for Human Virology, Baltimore, MD 21201.
authors: George K
authors: GK
authors: Lewis
authors: Institute for Human Virology, Baltimore, MD 21201.
authors: Anthony L
authors: AL
authors: DeVico
authors: Institute for Human Virology, Baltimore, MD 21201 rgallo@ihv.umaryland.edu fouts@profectusbiosciences.net.
authors: Robert C
authors: RC
authors: Gallo
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D056724:Immunity, Humoral; D008253:Macaca mulatta; D008297:Male; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: D016915:AIDS Vaccines; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011993:Recombinant Fusion Proteins; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: ADCC; FLSC; HIV vaccine; SIV challenge; protection