Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen (original) (raw)
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A Rationally Engineered Anti-HIV Peptide Fusion Inhibitor with Greatly Reduced Immunogenicity
Antimicrobial Agents and Chemotherapy, 2013
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International Immunopharmacology, 2009
To be effective, vaccines against the highly variable HIV-1 must elicit antibodies to a huge number of clinical isolates. For this purpose, new strategies to overcome this variability are needed. We previously reported a useful immunogenic strategy which consists of conjugating multiple antigen peptides (MAPs) to HBsAg. This vaccine candidate reduces the dose of immunogen required and increases the cross-reactivity towards other HIV strains. In the present study, we have expanded on those results by working with other carrier proteins. Thus, JY1-peptide (V3 regions of gp120 of HIV-1, subtype D) and JY1-MAP8 were synthesized and coupled to several carrier proteins such as KLH, HBsAg and P64k (recombinant meningococcal protein). Mice were immunized with various conjugates and their antigenicity, immunogenicity, and the level of cross-reactivity to a panel of five heterologous V3 peptides were compared. Our results show that conjugate JY1-MAP8 were not only more immunogenic than conjugate, they were also more or equally as immunogenic as 4-fold more JY1-MAP8 alone. Furthermore, conjugates to HBsAg and KLH were more immunogenic than those to P64k. Moreover, conjugates to HBsAg, KLH and P64k showed enhanced cross-reactivity to heterologous V3 peptides compared to JY1-peptide and JY1-MAP8. The analysis showed that conjugate-based immunogens are more prompt to elicit immunogenicity and cross-reactivity. These results can find application in the development of HIV vaccine candidates.
Frontiers in Immunology
There is an urgent need for the development of potent vaccination regimens that are able to induce specific T and B cell responses against human immunodeficiency virus type 1 (HIV-1). Here, we describe the generation and characterization of a fusion antigen comprised of the HIV-1 envelope GP120 glycoprotein from clade C (GP120C) fused at its C-terminus, with the modified vaccinia virus (VACV) 14K protein (A27L gene) (termed GP120C14K). The design is directed toward improving the immunogenicity of the GP120C protein through its oligomerization facilitated by the fused VACV 14K protein that results in hexamer-like structures. Two different immunogens were generated: a recombinant GP120C14K fusion protein (purified from a stable CHO-K1 cell line) and a recombinant modified vaccinia virus Ankara (MVA) poxvirus vector expressing the GP120C14K fusion protein (termed MVA-GP120C14K). The GP120C14K fusion protein is recognized by broadly neutralizing antibodies (bNAbs) against HIV-1. In a murine model, a heterologous prime/boost immunization regimen with MVA-GP120C14K prime followed by adjuvanted GP120C14K protein boost generated stronger and polyfunctional HIV-1 Env-specific CD8 T cell responses when compared with the delivery of the monomeric GP120C form. Furthermore, the immunization protocol MVA-GP120C14K/GP120C14K elicited higher HIV-1 Env-specific T follicular helper cells, germinal center B cells and antibody responses than monomeric GP120. In addition, a similar MVA-GP120C14K prime/GP120C14K protein boost regimen performed in rabbits triggered high HIV-1-Env-specific IgG binding antibody titers that were capable of neutralizing HIV-1 pseudoviruses. The extent of HIV-1 neutralization was comparable Raman et al. Hexamer-Like GP120C14K Protein as HIV Immunogen to that elicited by the current standard GP140 SOSIP trimers from clades B and C when immunized as MVA-SOSIP prime/SOSIP protein boost regimen. Overall, the novel fusion antigen and the corresponding immunization scheme provided in this report can therefore be considered as potential vaccine strategies against HIV-1.
Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody
Science, 2016
An antibody to block viral fusion A small fraction of HIV-1–infected individuals develop broad and potent antibodies that bind the HIV-1 envelope protein (Env). These antibodies recognize a limited set of conserved epitopes on Env, such as Env's host receptor-binding site. Kong et al. now report a neutralizing antibody isolated from an HIV-1–infected individual that binds to the fusion peptide of Env. This is unexpected because viruses often try to mask such key components of their cell entry machinery from antibody attack. Crystal structures of the antibody bound to the fusion peptide and to Env itself define the epitope, provide insight into the specific mechanism of antibody binding, and may inform HIV-1 vaccine design. Science , this issue p. 828
Understanding Biology Using Peptides
The identification of human monoclonal antibodies (mAbs) able to neutralize a broad spectrum of primary HIV-1 isolates is highly important for understanding the immune response of HIV-1 infection and developing vaccines and therapeutics. In this study, we isolated a novel human mAb termed Y498 from a phage display antibody library constructed with the PBMC samples of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity. Y498 cross-reacted with diverse Env antigens and neutralized 30% of 70 tested HIV-1 isolates. It efficiently blocked the binding of soluble CD4 to gp120 and competed with the CD4-binding site (CD4bs)specific mAbs. By combining molecular docking and site-directed mutagenesis, the epitope of Y498 was characterized to contain three antigenic sites on gp120, including the CD4 binding loop in C3, the β23 in C4 and the β24-α5 in C5, which overlap the binding sites of CD4 and CD4bs-directed mAbs (b12, VRC01, A16). Therefore, Y498 is a novel neutralizing human mAb targeting a conformation-dependent CD4bs-based epitope, and its isolation and characterization could provide helpful information for elucidating human immune response to HIV-1 infection and designing effective vaccines and immunotherapeutics.
Journal of Clinical Investigation, 1991
To make synthetic peptide vaccines effective in a broad population of outbred humans, one would have to incorporate enough antigenic determinants to elicit recognition by T cells of most HLA types. We have previously defined multideterminant regions of the human immunodeficiency virus (HIV) envelope that include overlapping determinants seen by proliferating T cells of three or four haplotypes of mice. We have now tested the hypothesis that synthetic peptides encompassing such multideterminant regions will be recognized by T cells of multiple murine MHC types as well as by human T cells representing multiple HLA types. Six such peptides of 20-33 residues in length were prepared, and tested for their ability to stimulate T cells from mice of four distinct MHC types immunized with recombinant envelope protein rgpl6O, as well as from 42 HIVinfected humans of different HLA types. Results identify several such peptides that are broadly recognized by mice of four H-2 types and by 52-73% of infected humans who still retain IL-2 productive responses to control recall antigens such as influenza A virus or tetanus toxoid. 86% of such infected donors tested against at least three peptides respond to at least one of the six peptides, and 77% of an additional group of seropositives respond to a mixture of the peptides. Moreover, the peptides can be used to immunize mice to elicit T cells reactive with the intact HIV envelope protein. These peptides therefore may be useful for both vaccine development in the broad human population, and diagnostic or prognostic use. (J. Clin. Invest.
Proceedings of the National Academy of Sciences, 1991
The generation of antiviral cytotoxic T lymphocytes (CTLs) is a critical component of the immune response to viral infections. A safe and nontoxic vaccine for AIDS would optimally use a carrier-free synthetic peptide immunogen containing only components of HIV necessary for induction of protective immune responses. We report that hybrid synthetic peptides containing either a HIV envelope gp120 T-cell determinant (T1) or the envelope gp41 fusion domain (F) N-terminal to HIV CTL determinants are capable of priming murine CD8+, major histocompatibility complex class I-restricted anti-HIV CTLs in vivo. These data demonstrate that carrier-free, nonderivatized synthetic peptides can be used in vivo to induce anti-HIV CTL responses.