Anne Bet1, Sarah Sterrett, Alicia Sato, Anju Bansal, Paul A Goepfert. 1. *Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL; †Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA; and ‡Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
Abstract
INTRODUCTION: Cryptic epitopes (CEs) can be encoded by any of the 5 alternative reading frames (ARFs, 2 sense and 3 antisense) of a known gene. Although CE responses are commonly detected during HIV-1 infection, it is not known whether these responses are induced after vaccination. METHODS: Using a bioinformatic approach, we determined that vaccines with codon-optimized HIV inserts significantly skewed CE sequences and are not likely to induce crossreactive responses to natural HIV CE. We then evaluated the CE- and protein-specific T-cell responses using Gag, Pol, and ARF peptide pools among participants immunized with a non-codon optimized vaccine regimen of 2 pGA2/JS7 DNA primes followed by 2 MVA/HIV62 Gag-Pol-Env vector boosts or 4 saline injections. RESULTS: Vaccinees had significantly more interferon gamma enzyme-linked immunosorbent spot (IFNγ ELISpot) responses toward Gag (P = 0.003) but not toward Pol protein than did placebo recipients. However, CE-specific T-cell responses were low in magnitude, and their frequencies did not differ significantly between vaccine and placebo recipients. Additionally, most positive CE responses could not be mapped to individual peptides. After expanding responses in a cultured assay, however, the frequency and the median magnitude of responses to ARF peptides were significantly greater in vaccinees (P < 0.0001), indicating that CE-specific T-cell responses are present but below an ex vivo assay's limit of detection. CONCLUSIONS: Our data demonstrate that HIV-1 vaccines currently in clinical trials are poorly immunogenic with regard to CE-specific T-cell responses. Therefore, the context of HIV-1 immunogens may need to be modified as a comprehensive strategy to broaden vaccine-induced T-cell responses.
INTRODUCTION:Cryptic epitopes (CEs) can be encoded by any of the 5 alternative reading frames (ARFs, 2 sense and 3 antisense) of a known gene. Although CE responses are commonly detected during HIV-1 infection, it is not known whether these responses are induced after vaccination. METHODS: Using a bioinformatic approach, we determined that vaccines with codon-optimized HIV inserts significantly skewed CE sequences and are not likely to induce crossreactive responses to natural HIV CE. We then evaluated the CE- and protein-specific T-cell responses using Gag, Pol, and ARFpeptide pools among participants immunized with a non-codon optimized vaccine regimen of 2 pGA2/JS7 DNA primes followed by 2 MVA/HIV62 Gag-Pol-Env vector boosts or 4 saline injections. RESULTS: Vaccinees had significantly more interferon gamma enzyme-linked immunosorbent spot (IFNγ ELISpot) responses toward Gag (P = 0.003) but not toward Pol protein than did placebo recipients. However, CE-specific T-cell responses were low in magnitude, and their frequencies did not differ significantly between vaccine and placebo recipients. Additionally, most positive CE responses could not be mapped to individual peptides. After expanding responses in a cultured assay, however, the frequency and the median magnitude of responses to ARF peptides were significantly greater in vaccinees (P < 0.0001), indicating that CE-specific T-cell responses are present but below an ex vivo assay's limit of detection. CONCLUSIONS: Our data demonstrate that HIV-1 vaccines currently in clinical trials are poorly immunogenic with regard to CE-specific T-cell responses. Therefore, the context of HIV-1 immunogens may need to be modified as a comprehensive strategy to broaden vaccine-induced T-cell responses.
Authors: James M Smith; Rama Rao Amara; David Campbell; Yan Xu; Milloni Patel; Sunita Sharma; Salvatore T Butera; Dennis L Ellenberger; Hong Yi; Lakshmi Chennareddi; James G Herndon; Linda S Wyatt; David Montefiori; Bernard Moss; Harold M McClure; Harriet L Robinson Journal: AIDS Res Hum Retroviruses Date: 2004-12 Impact factor: 2.205
Authors: Nel Otting; Corrine M C Heijmans; Riet C Noort; Natasja G de Groot; Gaby G M Doxiadis; Jon J van Rood; David I Watkins; Ronald E Bontrop Journal: Proc Natl Acad Sci U S A Date: 2005-01-21 Impact factor: 11.205
Authors: Yoshinori Fukazawa; Haesun Park; Mark J Cameron; Francois Lefebvre; Richard Lum; Noel Coombes; Eisa Mahyari; Shoko I Hagen; Jin Young Bae; Marcelo Delos Reyes; Tonya Swanson; Alfred W Legasse; Andrew Sylwester; Scott G Hansen; Andrew T Smith; Petra Stafova; Rebecca Shoemaker; Yuan Li; Kelli Oswald; Michael K Axthelm; Adrian McDermott; Guido Ferrari; David C Montefiori; Paul T Edlefsen; Michael Piatak; Jeffrey D Lifson; Rafick P Sékaly; Louis J Picker Journal: Nat Med Date: 2012-09-09 Impact factor: 53.440
Authors: Binghao J Peng; Jonathan M Carlson; Michael K P Liu; Feng Gao; Nilu Goonetilleke; Andrew J McMichael; Persephone Borrow; Jill Gilmour; Sonya L Heath; Eric Hunter; Anju Bansal; Paul A Goepfert Journal: J Virol Date: 2018-09-12 Impact factor: 5.103
Authors: Anju Bansal; Tiffanie Mann; Sarah Sterrett; Binghao J Peng; Anne Bet; Jonathan M Carlson; Paul A Goepfert Journal: J Acquir Immune Defic Syndr Date: 2015-09-01 Impact factor: 3.731