PMID- 28701395
OWN - NLM
STAT- MEDLINE
DCOM- 20170901
LR  - 20180502
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 91
IP  - 18
DP  - 2017 Sep 15
TI  - Preferential Targeting of Conserved Gag Regions after Vaccination with a
      Heterologous DNA Prime-Modified Vaccinia Virus Ankara Boost HIV-1 Vaccine
      Regimen.
LID - e00730-17 [pii]
LID - 10.1128/JVI.00730-17 [doi]
AB  - Prime-boost vaccination strategies against HIV-1 often include multiple variants 
      for a given immunogen for better coverage of the extensive viral diversity. To
      study the immunologic effects of this approach, we characterized breadth,
      phenotype, function, and specificity of Gag-specific T cells induced by a
      DNA-prime modified vaccinia virus Ankara (MVA)-boost vaccination strategy, which 
      uses mismatched Gag immunogens in the TamoVac 01 phase IIa trial. Healthy
      Tanzanian volunteers received three injections of the DNA-SMI vaccine encoding a 
      subtype B and AB-recombinant Gagp37 and two vaccinations with MVA-CMDR encoding
      subtype A Gagp55 Gag-specific T-cell responses were studied in 42 vaccinees using
      fresh peripheral blood mononuclear cells. After the first MVA-CMDR boost,
      vaccine-induced gamma interferon-positive (IFN-gamma(+)) Gag-specific T-cell
      responses were dominated by CD4(+) T cells (P < 0.001 compared to CD8(+) T cells)
      that coexpressed interleukin-2 (IL-2) (66.4%) and/or tumor necrosis factor alpha 
      (TNF-alpha) (63.7%). A median of 3 antigenic regions were targeted with a
      higher-magnitude median response to Gagp24 regions, more conserved between prime 
      and boost, compared to those of regions within Gagp15 (not primed) and Gagp17
      (less conserved; P < 0.0001 for both). Four regions within Gagp24 each were
      targeted by 45% to 74% of vaccinees upon restimulation with DNA-SMI-Gag matched
      peptides. The response rate to individual antigenic regions correlated with the
      sequence homology between the MVA- and DNA Gag-encoded immunogens (P = 0.04, r(2)
      = 0.47). In summary, after the first MVA-CMDR boost, the sequence-mismatched
      DNA-prime MVA-boost vaccine strategy induced a Gag-specific T-cell response that 
      was dominated by polyfunctional CD4(+) T cells and that targeted multiple
      antigenic regions within the conserved Gagp24 protein.IMPORTANCE Genetic
      diversity is a major challenge for the design of vaccines against variable
      viruses. While including multiple variants for a given immunogen in prime-boost
      vaccination strategies is one approach that aims to improve coverage for global
      virus variants, the immunologic consequences of this strategy have been poorly
      defined so far. It is unclear whether inclusion of multiple variants in
      prime-boost vaccination strategies improves recognition of variant viruses by T
      cells and by which mechanisms this would be achieved, either by improved
      cross-recognition of multiple variants for a given antigenic region or through
      preferential targeting of antigenic regions more conserved between prime and
      boost. Engineering vaccines to induce adaptive immune responses that
      preferentially target conserved antigenic regions of viral vulnerability might
      facilitate better immune control after preventive and therapeutic vaccination for
      HIV and for other variable viruses.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Bauer, Asli
AU  - Bauer A
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany.
FAU - Podola, Lilli
AU  - Podola L
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany.
FAU - Mann, Philipp
AU  - Mann P
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany.
FAU - Missanga, Marco
AU  - Missanga M
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
FAU - Haule, Antelmo
AU  - Haule A
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
FAU - Sudi, Lwitiho
AU  - Sudi L
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
FAU - Nilsson, Charlotta
AU  - Nilsson C
AD  - Public Health Agency of Sweden, Solna, Sweden.
AD  - Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
FAU - Kaluwa, Bahati
AU  - Kaluwa B
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
FAU - Lueer, Cornelia
AU  - Lueer C
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany.
FAU - Mwakatima, Maria
AU  - Mwakatima M
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
FAU - Munseri, Patricia J
AU  - Munseri PJ
AD  - Department of Internal Medicine, Muhimbili University of Health and Allied
      Sciences, Dar es Salaam, Tanzania.
FAU - Maboko, Leonard
AU  - Maboko L
AD  - NIMR Mbeya Medical Research Center (MMRC), Mbeya, Tanzania.
FAU - Robb, Merlin L
AU  - Robb ML
AD  - United States Military HIV Research Program (MHRP), Bethesda, Maryland, USA.
FAU - Tovanabutra, Sodsai
AU  - Tovanabutra S
AD  - United States Military HIV Research Program (MHRP), Bethesda, Maryland, USA.
FAU - Kijak, Gustavo
AU  - Kijak G
AD  - United States Military HIV Research Program (MHRP), Bethesda, Maryland, USA.
FAU - Marovich, Mary
AU  - Marovich M
AD  - United States Military HIV Research Program (MHRP), Bethesda, Maryland, USA.
FAU - McCormack, Sheena
AU  - McCormack S
AD  - MRC Clinical Trials Unit at UCL, London, United Kingdom.
FAU - Joseph, Sarah
AU  - Joseph S
AD  - MRC Clinical Trials Unit at UCL, London, United Kingdom.
FAU - Lyamuya, Eligius
AU  - Lyamuya E
AD  - Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam,
      Tanzania.
FAU - Wahren, Britta
AU  - Wahren B
AD  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet,
      Stockholm, Sweden.
FAU - Sandstrom, Eric
AU  - Sandstrom E
AD  - Karolinska Institute, Stockholm, Sweden.
FAU - Biberfeld, Gunnel
AU  - Biberfeld G
AD  - Public Health Agency of Sweden, Solna, Sweden.
AD  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet,
      Stockholm, Sweden.
FAU - Hoelscher, Michael
AU  - Hoelscher M
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany.
AD  - German Center for Infection Research (DZIF), partner site Munich, Munich,
      Germany.
FAU - Bakari, Muhammad
AU  - Bakari M
AD  - Muhimbili University of Health and Allied Sciences (MUHAS), Dar es Salaam,
      Tanzania.
FAU - Kroidl, Arne
AU  - Kroidl A
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany.
AD  - German Center for Infection Research (DZIF), partner site Munich, Munich,
      Germany.
FAU - Geldmacher, Christof
AU  - Geldmacher C
AD  - Division of Infectious Diseases and Tropical Medicine, Medical Center of the
      University of Munich (LMU), Munich, Germany geldmacher@lrz.uni-muenchen.de.
AD  - German Center for Infection Research (DZIF), partner site Munich, Munich,
      Germany.
LA  - eng
GR  - MC_U122861400/Medical Research Council/United Kingdom
GR  - MRC_UU_12023/23/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170824
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (AIDS Vaccines)
RN  - 0 (Drug Carriers)
RN  - 0 (IL2 protein, human)
RN  - 0 (Interleukin-2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vaccines, DNA)
RN  - 0 (Vaccines, Subunit)
RN  - 0 (Vaccines, Synthetic)
RN  - 0 (gag Gene Products, Human Immunodeficiency Virus)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - AIDS Vaccines/administration & dosage/*immunology
MH  - Drug Carriers
MH  - HIV-1/*immunology
MH  - Healthy Volunteers
MH  - Humans
MH  - Interferon-gamma/secretion
MH  - Interleukin-2/secretion
MH  - T-Lymphocyte Subsets/immunology
MH  - T-Lymphocytes/*immunology
MH  - Tanzania
MH  - Tumor Necrosis Factor-alpha/secretion
MH  - Vaccination/*methods
MH  - Vaccines, DNA/administration & dosage/*immunology
MH  - Vaccines, Subunit/administration & dosage/immunology
MH  - Vaccines, Synthetic/administration & dosage/immunology
MH  - Vaccinia virus/genetics
MH  - gag Gene Products, Human Immunodeficiency Virus/*immunology
PMC - PMC5571275
OTO - NOTNLM
OT  - *Gag
OT  - *T cells
OT  - *human immunodeficiency virus
OT  - *vaccines
EDAT- 2017/07/14 06:00
MHDA- 2017/09/02 06:00
CRDT- 2017/07/14 06:00
PHST- 2017/05/18 00:00 [received]
PHST- 2017/06/14 00:00 [accepted]
PHST- 2017/07/14 06:00 [pubmed]
PHST- 2017/09/02 06:00 [medline]
PHST- 2017/07/14 06:00 [entrez]
AID - JVI.00730-17 [pii]
AID - 10.1128/JVI.00730-17 [doi]
PST - epublish
SO  - J Virol. 2017 Aug 24;91(18). pii: JVI.00730-17. doi: 10.1128/JVI.00730-17. Print 
      2017 Sep 15.