CD4+ T Cells Induced by Tuberculosis Subunit Vaccine H1 Can Improve the HIV-1 Env Humoral Response by Intrastructural Help.

Stephan Klessing,Dennis Christensen,Klaus Überla,Roland Lang,Antonia Sophia Peter,Vladimir Temchura,Pierre Tannig

doi:10.3390/vaccines8040604

Stephan Klessing, Dennis Christensen + Show 5 more

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https://doi.org/10.3390/vaccines8040604

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The induction of a potent and long-lasting, broadly neutralizing antibody response is one of the most promising approaches in HIV-1 vaccination. Recently, we demonstrated that Gag-specific T helper cells induced by DNA priming can enhance and modulate the HIV Env-specific B cell response upon virus-like particle (VLP) boost by intrastructural help (ISH). In order to minimize the induction of potentially harmful HIV specific TH cells, we explored the possibility to harness the heterologous TH cells induced by a recombinant tuberculosis subunit vaccine H1, which contains a fusion protein of Ag85B and ESAT-6 antigens in combination with the liposomal adjuvant CAF01. To provide ISH, immunodominant MHC-II restricted peptides from the H1 vaccine were genetically incorporated into the HIV 1 Gag protein and used for HIV VLP production. ISH effects on Env-specific antibody levels and B cell differentiation were analyzed in mice primed against H1 and boosted with VLPs. In contrast to non-primed mice, a significant increase of Env-specific IgG levels for up to 26 weeks after the last immunization was observed. This increase was largely caused by elevated IgG2b and IgG2c levels in mice that received H1 priming. Additionally, ISH enhanced the frequency of Env-specific long-lived plasma cells in the bone marrow. In this study, we were able to demonstrate that a heterologous prime-boost regimen consisting of the H1 tuberculosis subunit vaccine and T helper epitope modified HIV-1 VLPs resulted in enhanced HIV Env antibody and B cell responses, mediated by intrastructural help.

Highlights

Over the course of the last decades, there has been substantial worldwide effort in the development of a prophylactic HIV-1 vaccine
Tetanus DNA control priming led to a modest increase of TH 1 associated IgG2a levels, setting focus on the T cell response induced by different vaccinations in the context of intrastructural help (ISH)
We investigate whether the induction of a TH 1-dominated primary T cell response can mediate a shift by ISH towards a more desirable IgG2c-dominated Env-specific antibody response

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Introduction

Over the course of the last decades, there has been substantial worldwide effort in the development of a prophylactic HIV-1 vaccine. Until now, most of the conducted clinical trials failed to confer protection [1]. The RV144 vaccine trial showed an estimated efficacy of 60.5% six months after vaccination, which rapidly declined to 31.2% during the following 2.5 years [2,3]. It is generally believed that an induction of potent and long-lasting, broadly neutralizing antibody (bNab) response poses a highly promising approach in HIV vaccination. It was previously observed that bNAbs against Env, which are thought to act in a Fab-dependent manner, rely on subclass- and FcR-dependent mechanisms in different in vivo models [4,5].

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