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.
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.
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.
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.
*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.
Correspondence to: Paul A. Goepfert, MD, Department of Medicine, University of Alabama at Birmingham, 908 20th Street South CCB 328, Birmingham, AL 35294 (e-mail: firstname.lastname@example.org).
Supported by NIAID: RO1 A1 084772 (Goepfert).
Presented HIV-1 Vaccine codon optimization: Implications for the development of CD8 T-cell responses. (OA01.02) Global HIV Vaccine Enterprise's 2010 AIDS Vaccine Meeting. Atlanta, GA. 2010. Characterization of T cell responses to cryptic epitopes in recipients of a non-codon optimized HIV-1 vaccine. (179.10, P4495) AAI's 100th Annual Meeting: IMMUNOLOGY 2013. Honolulu, HA. 2013.
The authors have no conflicts of interest to disclose.
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Received May 01, 2013
Accepted August 15, 2013