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© Research
Member: Permanent Researcher

Timothée Bruel

• Virus and Immunity

About

My work focuses on the antiviral activities of antibodies against HIV-1 and SARS-CoV-2.

Despite the success of anti-retroviral therapy (ART) to treat HIV-1-infected individuals, the persistence of a viral reservoir remains an obstacle to a cure. Characterization of the antibody repertoire in patients led to the identification of broadly neutralizing antibodies (bNAbs) targeting the viral envelope glycoproteins and suppressing HIV-1 infectivity with unprecedented potency. Passive administration of bNAbs in animal models or in infected humans revealed their capacity to decrease viral loads and to delay viral rebound after ART cessation. bNAbs also activate the immune system and mediate functions that go well beyond neutralization, such as killing of infected cells or enhancement of T and B cell responses. The molecular and cellular mechanisms underlying the activation of Fc-dependent effector functions of antibodies, including bNAbs, are incompletely understood.

My aim is to analyze the interactions between HIV-1 specific antibodies, infected cells, and the immune system.

Example of HIV-1-infected cell killing by NK cells: An HIV-1-infected cell (green) and NK cell (smaller dark cells) are trapped in a microwells and recorded. A picture is taken every 5 minutes. A blue dye reveals the dying cell

Antibodies targeting the Spike (S) protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) contribute to vaccine efficacy and are used as therapy against Coronavirus Disease 2019 (COVID-19). They act by neutralizing viral replication, but also by recruiting immune effector mechanisms. These so-called non-neutralizing activities are required for optimal therapeutic efficacy of monoclonal antibodies, but their molecular and cellular mechanisms are poorly understood. The emergence of SARS-CoV-2 variants demonstrated convergent evolution in regions targeted by antibodies. These variants of concerns (VOCs) have an increased replicative capacity and can partially escape neutralizing antibodies, challenging our capacity to contain COVID-19 pandemic. Thus, a better understanding of the neutralizing and non-neutralizing antiviral activities of antibodies with regard of viral diversity is needed.

My goal is to define the landscape of antibody antiviral activities against SARS-CoV-2, characterize their impact on viral replication, and identify the underlying regulatory mechanisms. I will first determine how viral and cellular proteins modulate antibody recognition of infected cells, and how it subsequently influences antibody-mediated cellular cytotoxicity (ADCC). Next, I will study how antibodies recruit complement and phagocytic cells to clear viral particles and determine whether the virus hijacks cellular proteins for protection. Finally, I will analyse the susceptibility of VOCs and some of their circulating sublineages to neutralizing and non-neutralizing antibody functions.

Overall, my projects aim at providing a basic understanding of antibody polyfunctionality and associated viral countermeasures, with implications for the development of the next generations of antibody-based vaccines and therapies.

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