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Neutralizing antibodies against HIV-1: can we elicit them with vaccines and how much do we need?

ABSTRACT: This review describes some of the major obstacles that have impeded progress in the development of an effective neutralizing antibody-based HIV-1 vaccine and explains why it may be possible to overcome these obstacles. A renewed interest in the B-cell response in HIV-1-infected individuals is emphasized.New assay technologies and access to large numbers of clinical specimens have permitted a detailed assessment of the neutralizing antibody response in HIV-1-infected individuals. Recent studies have demonstrated that B cells can be stimulated to generate high titers of broadly cross-reactive neutralizing antibodies against multiple genetic subtypes of the virus. Preliminary evidence suggests that some of these antibodies are directed against epitopes in the CD4 binding site on monomeric gp120, whereas many others are directed against epitopes that remain to be identified.The rationale for pursuing an effective neutralizing antibody-based HIV-1 vaccine is strengthened by the recent demonstration of potent neutralizing antibody responses in a subset of HIV-1-infected individuals. Information on how this response develops and what epitopes are targeted could provide the insights that are needed to design improved vaccine strategies.

SUBMITTER: Montefiori DC

PROVIDER: S-EPMC2879149 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Neutralizing antibodies against HIV-1: can we elicit them with vaccines and how much do we need?

Montefiori David C DC Mascola John R JR

Current opinion in HIV and AIDS 20090901 5

<h4>Purpose of review</h4>This review describes some of the major obstacles that have impeded progress in the development of an effective neutralizing antibody-based HIV-1 vaccine and explains why it may be possible to overcome these obstacles. A renewed interest in the B-cell response in HIV-1-infected individuals is emphasized.<h4>Recent findings</h4>New assay technologies and access to large numbers of clinical specimens have permitted a detailed assessment of the neutralizing antibody respon ...[more]

PMID: 20048696

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Project description:A vaccine regimen that elicits broadly neutralizing antibodies (bNAbs) is a major goal in HIV-1 vaccine research. In this study, we assessed the immunogenicity of the CAP256 superinfecting viral envelope (CAP256 SU) protein delivered by modified vaccinia virus Ankara (MVA) and DNA vaccines in different prime-boost combinations followed by a soluble protein (P) boost. The envelope protein (Env) contained a flexible glycine linker and I559P mutation. Trimer-specific bNAbs PGT145, PG16, and CAP256 VRC26_08 efficiently bound to the membrane-bound CAP256 envelope expressed on the surface of cells transfected or infected with the DNA and MVA vaccines. The vaccines were tested in two different vaccination regimens in rabbits. Both regimens elicited autologous tier 2 neutralizing antibodies (NAbs) and high-titer binding antibodies to the matching CAP256 Env and CAP256 V1V2 loop scaffold. The immunogenicity of DNA and MVA vaccines expressing membrane-bound Env alone was compared to that of Env stabilized in a more native-like conformation on the surface of Gag virus-like particles (VLPs). The inclusion of Gag in the DNA and MVA vaccines resulted in earlier development of tier 2 NAbs for both vaccination regimens. In addition, a higher proportion of the rabbits primed with DNA and MVA vaccines that included Gag developed tier 2 NAbs than did those primed with vaccine expressing Env alone. Previously, these DNA and MVA vaccines expressing subtype C mosaic HIV-1 Gag were shown to elicit strong T cell responses in mice. Here we show that when the CAP256 SU envelope protein is included, these vaccines elicit autologous tier 2 NAbs.IMPORTANCE A vaccine is urgently needed to combat HIV-1, particularly in sub-Saharan Africa, which remains disproportionately affected by the AIDS pandemic and accounts for the majority of new infections and AIDS-related deaths. In this study, two different vaccination regimens were compared. Rabbits that received two DNA primes followed by two modified vaccinia virus Ankara (MVA) and two protein inoculations developed better immune responses than those that received two MVA and three protein inoculations. In addition, DNA and MVA vaccines that expressed mosaic Gag VLPs presenting a stabilized Env antigen elicited better responses than Env alone, which supports the inclusion of Gag VLPs in an HIV-1 vaccine.

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Neutralizing antibodies against HIV-1: can we elicit them with vaccines and how much do we need?

Publications

Neutralizing antibodies against HIV-1: can we elicit them with vaccines and how much do we need?

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