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About the research performed at the VRI on the Impact of vaccines and HIV on the innate and adaptive immune response

The objective of the BASIC division is to better understand the molecular mechanisms of HIV vaccines developed in the VRI. The research work performed in the groups provides detailed molecular and cellular frameworks that helps to understand how VRI vaccines generate efficient immune response. The group also searches for weaknesses in the current vaccines, opening the door for improved next-generation VRI vaccination strategies. The group is composed of 5 teams.
As part of this research, Nicolas Manel and his team (Innate immunity Unit, Inserm U932, Institut Curie)are interested in the interaction of a candidate vaccine developed by the VRI and the ANRS, MVA, with dendritic cells (DCs), the signaling induced by this vaccine in DCs and T cell response induced following this signaling. The relationship between DCs infected by MVA and by-stander DC is under characterization.
In addition, thanks to innovative technologies, Philippe Bousso and his team (Dynamics of Immune Responses Unit, Institut Pasteur, Inserm U1223) have managed to film in vivo the triggering of the immune response by the MVA vaccine candidate developed by the VRI and the ANRS. This showed the precise action of the vaccine on the recruitment of immune cells necessary for the destruction of infected cells.
Beyond their prophylactic effect, broadly neutralizing antibodies (bNAbs) might be of importance in the therapeutic arsenal against HIV. Olivier Schwartz and his team (Virus and Immunity Unit, Institut Pasteur), in collaboration with Hugo Mouqet are investigating the antiviral and vaccine-like properties of bNAbs. They identified bNAbs that exert Antibody-dependent Cellular Cytotoxicity (ADCC) in cell culture and kill HIV-1-infected lymphocytes through NK cell engagement. Their study delineates the parameters controlling ADCC activity of bNAbs, and supports the use of the most potent Abs to clear the viral reservoir.
Jim di Santo and his team (Innate Immunity Unit, Institut Pasteur, Inserm U1223) are assessing the effect of combining MVA and bNAb in a preclinical therapeutic model of HIV infection. The results obtained are encouraging and showed a better control of viral replication when MVA and bNAb are combined in a therapeutic HIV setting and highlights the importance of combined immunotherapeutic strategies to control viral rebounds.
Hugo Mouquet and his team (Humoral Response to Pathogens Unit, Institut Pasteur, Inserm U1222) join the BASIC division in 2019, which will foster the development of interactions between bnAbs and candidate vaccines in the VRI.

3 questions to Nicolas MANEL

nicolas manelNicolas Manel, co-leader of the VRI basic division, Innate immunity Unit, Inserm U932, Institut Curie, who recently published a paper in Cell “NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation“  

 

What is the protein NONO and its role in HIV pathogenesis?
NONO is an innate immune sensor of the HIV capsid protein: NONO detects the presence of the virus in infected cells and activates an immune response. This discovery is important because it helps to answer a long-lasting question: why is HIV-1 so pathogenic? HIV-1 is not well recognized by NONO. As a result, we think that the immune system is not well activated to eliminate or control the virus. In contrast, NONO recognizes very well the capsid of HIV-2, a related virus mainly found in west Africa that is much less pathogenic and that triggers a potent immune response. Thus, humans possess the necessary proteins to detect the virus and induce a potent immune response – NONO – but HIV-1 evades this detection, which we think helps to explain why this virus is so pathogenic.

What could be the impact of your discovery for a vaccine against HIV?
NONO illuminates a critical molecular immune pathway that is highly desirable to activate in HIV vaccines. In the short-term, this is a new molecular target to evaluate in HIV vaccines: how efficiently is the NONO pathway activated by HIV vaccines? In parallel, this discovery opens the door to build next-generation HIV vaccines that would directly and strongly activate NONO, thus inducing a strong immune response against the virus.

What is the follow up of your study?

We follow two main questions:

 

  • First, how is the NONO machinery working at the molecular level to recognize HIV and activate the immune response? To address this, we are performing a detailed molecular characterization of the pathway. This is essential to develop new vaccines or drugs that could directly activate it.

 

  • Second, NONO interestingly recognizes a specific protein of HIV, the capsid – and capsids are a very common feature of many, if not all, viruses. Are other viruses recognized by NONO, or similar other proteins? We think that HIV is the tip of the iceberg, and that this new paradigm of viral sensing by the innate immune sensing will be broadly applicable to many other viruses.

 

What should you know about preclinical model at VRI?

After more than 30 years of intensive research in HIV, the highly efficacious vaccine and/or immunotherapies that could prevent HIV infection and/or the occurrence of AIDS is still needed as well as animal models able to predict HIV vaccine or immunotherapy efficacy in humans. The recent development of humanized mice with a functional human immune system (HIS) may help to improve our understanding of HIV-1 pathogenesis and lead to new treatments. These mice are invaluable for several aspects of HIV-1 research, especially to study immune responses and immunopathogenesis, and to test immunotherapies or new innovative vaccines for HIV prevention and treatment.
Substantial advances have been made in developing optimal HIS mouse models since the first report 30 years ago (McCune et al., 1988). Since then, efforts in the field have been made to improve the functions of the human cells in these chimeric mice.
The VRI has taken opportunity of the availability of these new HIS mice to explore the feasibility of using these preclinical models to test candidate vaccines in a combinatorial approach.
Guillemette Masse-Ranson (Innate Immunity Unit, Institut Pasteur, Inserm U1223 & U955 team 16 UPEC) has developed a series of novel HIS models with enhanced innate and adaptive human immune responses. Using HIV-infected HIS models, she is testing novel combinatorial immunotherapies involving ANRS MVA-HIVB and broadly neutralizing antibodies (bNAbs) developed by Hugo Mouquet and his team (Humoral Response to Pathogens Unit, Institut Pasteur, Inserm U1222) that can potentially target HIV reservoirs in vivo.
In parallel, Veronique Godot (INSERM Unit U955, Team 16, UPEC) evaluates in HIS mice the effectiveness of anti-HIV-1 vaccines that specifically target antigen-presenting cells (e.g. dendritic cells) bringing them HIV-1 antigens and activating them. In collaboration with Gerard Zurawski (Baylor Institute for Immunology Research, USA), Lishan Su (University of Norht Carolina, USA), Giuseppe Pantaleo (Centre Hospitalier Universitaire Vaudois, Switzerland & Inserm U955 team 16, UPEC) and their respective teams, she is testing the ability of anti-CD40.Env gp140 prophylactic vaccine to elicit potent HIV-1 specific B cell immune responses in order to prevent HIV-1 infection in HIS mice in homologous and heterologous prime boost strategies with the NYVAC-KC.Env gp140 vaccine. The anti-CD40.Env gp140 vaccine will be tested in further studies in prime-boost combination with DNA-HIV-PT123 and ANRS-MVA HIVB vaccine.
Guillemette and Véronique have joined forces to further increase the potential exploitation of such preclinical HIS mice for combinatorial vaccine approach at the VRI.