A Vaccine Encoding Conserved Promiscuous HIV CD4 Epitopes Induces Broad T Cell Responses in Mice Transgenic to Multiple Common HLA Class II Molecules

et al. (2010) A Vaccine Encoding Conserved Promiscuous HIV CD4 Epitopes Induces Broad T Cell Responses in Mice Transgenic to Multiple Common HLA Class II Molecules. PLoS ONE 5(6): e11072. doi:10.1371/journal.pone.0011072 A Vaccine Encoding Conserved Promiscuous HIV CD4 Epitopes Induces Broad T Cell Responses in Mice Transgenic to Multiple Common HLA Class II Molecules Susan Pereira Ribeiro 0 Daniela Santoro Rosa 0 Simone Gonc alves Fonseca 0 Eliane Conti 0 Mairena 0 Edilberto Posto l 0 Sergio Costa Oliveira 0 Luiza Guilherme 0 Jorge Kalil 0 Edecio Cunha-Neto 0 Mario A. Ostrowski, University of Toronto, Canada 0 1 Laboratory of Clinical Immunology and Allergy-LIM60, Division of Clinical Immunology and Allergy, Department of Medicine, University of Sa o Paulo School of Medicine, Sa o Paulo, Brazil, 2 Heart Institute (InCor), University of Sa o Paulo School of Medicine, Sa o Paulo, Brazil, 3 Institute for Investigation in Immunology-INCT, Sa o Paulo, Brazil, 4 Department of Biochemistry and Immunology, Federal University of Minas Gerais , Belo Horizonte , Brazil Current HIV vaccine approaches are focused on immunogens encoding whole HIV antigenic proteins that mainly elicit cytotoxic CD8+ responses. Mounting evidence points toward a critical role for CD4+ T cells in the control of immunodeficiency virus replication, probably due to cognate help. Vaccine-induced CD4+ T cell responses might, therefore, have a protective effect in HIV replication. In addition, successful vaccines may have to elicit responses to multiple epitopes in a high proportion of vaccinees, to match the highly variable circulating strains of HIV. Using rational vaccine design, we developed a DNA vaccine encoding 18 algorithm-selected conserved, ''promiscuous'' (multiple HLA-DR-binding) B-subtype HIV CD4 epitopes - previously found to be frequently recognized by HIV-infected patients. We assessed the ability of the vaccine to induce broad T cell responses in the context of multiple HLA class II molecules using different strains of HLA class II- transgenic mice (-DR2, -DR4, -DQ6 and -DQ8). Mice displayed CD4+ and CD8+ T cell responses of significant breadth and magnitude, and 16 out of the 18 encoded epitopes were recognized. By virtue of inducing broad responses against conserved CD4+ T cell epitopes that can be recognized in the context of widely diverse, common HLA class II alleles, this vaccine concept may cope both with HIV genetic variability and increased population coverage. The vaccine may thus be a source of cognate help for HIV-specific CD8+ T cells elicited by conventional immunogens, in a wide proportion of vaccinees. - Funding: This research was supported by the Brazilian National Research Council (CNPq), Sao Paulo State Research Funding Agency (FAPESP), International Centre of Genetic Engineering and Biotechnology (ICGEB) and from the Brazilian Ministry of Health (Brazil). S. P. Ribeiro and D. S. Rosa are recipients of a Sao Paulo State Research Funding Agency (FAPESP) fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The International Centre of Genetic Engineering and Biotechnology (ICGEB) is a non-profit organization related to the UNESCO which funds basic research in developing and middle-income countries. There are no links (employment, consultancy, patents, products in development or marketed products) between the authors and the ICGEB that may alter the authors adherence to all the PLoS ONE policies on sharing data and materials. The use of the peptide combination for vaccination purposes, among others, has been patented (international application number PCT/BR2006/000175). . These authors contributed equally to this work. Given the proportions of the AIDS pandemic, development of an effective vaccine against human immunodeficiency virus type 1 (HIV-1) remains one of the most important biomedical research priorities. Only three vaccine concepts have completed clinical efficacy studies so far, with two negative results (Env gp 120 vaccine -AIDSVAX; recombinant Adenovirus 5 HIV-1 gag/pol/ nef trivalent vaccine -STEP trial [1]), and one showing borderline efficacy, with no effect on HIV-1 viral load (recombinant canarypox ALVAC (gp120/Gag/Protease) prime - gp120 protein boost - ALVAC-AIDSVAX) [2]. Vaccination regimens that induced cell-mediated immunity were shown to significantly reduce simian immunodeficiency virus (SIV) replication in non-human primates [3], [4], [5]. Therefore, most of the HIV-1 vaccine field is currently focused on development of vaccines that elicit potent cytotoxic CD8+ responses. The lack of efficacy of the recently studied STEP trial of the Adenovirus 5 HIV-1 gag/pol/nef trivalent vaccine [6] may have been related to the narrowness of the induced T cell response on average, only one epitope was recognized per HIV-1 gene product in each vaccinee [7]. Recent evidence from the SIV infected macaque model show that heterozygote animals, which carry more MHC molecules and present a broader T cell response, display better control of viral load than their homozygote counterparts [8]. It has thus been argued that the development of novel vaccine strategies that elicit a greater epitope breadth, matching T cell responses to circulating HIV strains, is a critical step to improve effectiveness of a vaccine against the highly variable HIV-1 [7]. In addition, 30% and 60% of vaccinees in the STEP trial failed to display CD8+ and CD4+ T cell responses to HIV epitopes, respectively [9]. Regarding the ALVAC-AIDSVAX trial, no CD8+ T cell responses were detected among the vaccinees, and 66% of them failed to display CD4+ T cell responses to gp120 [2]. Thus, vaccines tested in recent efficacy trials failed to induce CD8+ and especially CD4+ T cell responses in a significant proportion of vaccinees. The lack of population coverage may thus have been another cause of the insufficient results of the trials. Thus, innovative vaccine antigen design and immunogen formulation is needed in order to develop a vaccine able to induce broad immune responses in the majority of vaccinees. One possible way to increase the breadth of the response would be to include most or all of the HIV-1 proteome into a viral vector [5]. However, most viral vectors pose constraints on insert size, and developing such a vaccine for large-scale use could be technically challenging or impractical. On the other hand, epitope-based vaccines combine multiple T cell epitopes assembled in tandem, and can focus the immune response on any chosen group of epitopes (e. g. conserved and highly antigenic), generating much smaller insert sizes. Every single epitope can be immunogenic in multiple epitope-based vaccines; in addition, they have been reported to generate broad and potent immune responses [10], [11], [12], [13], [14]. By eliminating epito (...truncated)