Broad and Cross-Clade CD4+ T-Cell Responses Elicited by a DNA Vaccine Encoding Highly Conserved and Promiscuous HIV-1 M-Group Consensus Peptides

Abstract

T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4+ T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4+ T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4+ T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IAb and IAd. Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-γ secretion against 11 out of the 27 peptides in BALB/c mice; CD4+ and CD8+ T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4+ and CD8+ T cells, able to simultaneously proliferate and produce IFN-γ and TNF-α, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS.

HIV-1 p24gag Derived Conserved Element DNA Vaccine Increases the Breadth of Immune Response in Mice

“…As a result, there is currently no candidate HIV vaccine that predictably elicits broad, durable and protective immune responses. To maximize immunologic breadth, several alternative approaches are being explored, including the use of consensus, ancestral or center-of-tree immunogens, multiple strains and mosaic immunogens, immunogens consisting of known epitopes from the database, algorithm-selected epitopes or a selection of the most conserved epitopes from different clades as one chimera [1]–[19]. It may not be possible to vaccinate with all of the viral antigenic diversity required to block viable or transitional escape forms of the virus [20], [21] because, to be practical, a vaccine should preferably consist of as few components as possible.…”

Bioinformatic prediction of epitopes in the Emy162 antigen of Echinococcus multilocularis

“…Epitopes comprise the fundamental structural subunits of the T- and B-cell antigen receptors (TCR and BCR, respectively), and the specific antibody-binding sites. Thus, epitopes may be classified as T- or B-cell epitopes (13,14). With the development of bioinformatic technology, epitope vaccines (15) have become increasingly important in immune prevention.…”

Chimeric porcine reproductive and respiratory syndrome virus containing shuffled multiple envelope genes confers cross-protection in pigs

“…Novel strategies for developing universal cross-protective vaccines have been explored for a number of antigenically highlyvariable viruses such as influenza virus and HIV based on highly conserved antigens (Almeida et al, 2012;Neirynck et al, 1999;Pica and Palese, 2013). For PRRSV, which is also genetically and antigenically highly variable, thus far there is no vaccine that can provide sufficient cross-protection against all heterologous strains (Li et al, 2014;Martelli et al, 2009).…”