David Zarzoso

Homam Betar

Diego Del-Castillo-Negrete

Jacobo Varela

Luis Garcia

Jeronimo Garcia

Yevgen Kazakov

D Spong

Jet Contributors

TRANSPORT AND LOSSES OF FUSION-BORN ALPHA PARTICLES IN THE PRESENCE OF MHD INSTABILITIES A passive tracer approach using the new full-orbit Toroidal Accelerated PArticle Simulator (TAPAS)

d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

TRANSPORT AND LOSSES OF FUSION-BORN ALPHA PARTICLES IN THE PRESENCE OF MHD INSTABILITIES

A passive tracer approach using the new full-orbit Toroidal Accelerated PArticle Simulator (TAPAS)

INTRODUCTION

Energetic particles are ubiquitous in present fusion plasmas, in particular energetic ions, which are born from the external heating, either Neutral Beam Injection (NBI) or Ion Cyclotron Resonant heating (ICRH). These ions exhibit energies much larger than the thermal velocity of the particles of the bulk plasma. Their presence ensures the heating of the thermal plasma by means of Coulomb collisions as well as the parallel current that can improve the confinement [1,2]. It is nonetheless expected that the main heating in future fusion reactors comes from the thermalization of energetic (3.5 MeV) alpha particles generated by the fusion reactions between Deuterium and Tritium. These fusion-born alpha particles will transfer their energy first to the electrons, and afterwards (when their energy is below the critical energy) to the ion population. However, the presence of highly energetic ions in the plasma (either accelerated by external heating or generated by fusion reactions) can trigger instabilities which can result in significant transport and eventual losses of energetic ions, reducing this way the performance of present and future tokamaks. Of special importance is the impact of these instabilities on the confinement of fusion-born alpha particles, since degradation of their confinement can be deleterious to the achievement of steady-state regimes of energy production. For this reason, it is essential to understand and quantify the transport and losses of fusion-born alpha particles in the presence of MHD instabilities. In this context, the second D-T campaign (DTE2) that took place at the JET tokamak has represented a unique opportunity to conduct in-depth analyses of alpha particle physics in D-T plasmas. In the paper, we perform analyses of the losses of fusion-born alpha particles by modelling the JET discharge 99896 [3]. In this discharge, Deuterium and Tritium NBI heating was applied one after the other and combined with ICRH. The destabilization of fishbones at f ∼ 40 kHz and Toroidicity-induced Alfvén Eigenmodes (TAEs) at f ∼ 150-190 kHz was observed. To study the impact on alpha particle confinement, we proceed in two steps. First, we conduct numerical modelling of the discharge 99896 by means of gyro-fluid simulations using FAR3d code [4]. The electromagnetic potential is then used to integrate trajectories of alpha particles using the full-orbit Toroidal Accelerated PArticle Simulator (TAPAS), updated from the original guiding-centre version [5]. It is to be noted that in the considered JET discharge, alpha particles do not drive any instability. Therefore, considering these particles as passive tracers in TAPAS is justified. The paper is structured as follows. Section 2 is devoted to describing the gyro-fluid modelling of the the JET discharge. In section 3 we provide an overview of the new TAPAS code. In section 4 we show the outcome of the analyses from the coupling FAR3d-TAPAS. Finally, in section 5 we summarize the results and give some future directions.

SUMMARY OF GYRO-FLUID MODELLING USING FAR3D CODE

The FAR3d code [4] evolves a set of reduced MHD equations for the thermal plasma, including Ohm's law, the parallel component of vorticity, pressure, and parallel velocity. Additionally, it includes two equations for each population of energetic particles: one for density and another for the parallel component of the energetic particle velocity. These latter equations are derived from the gyrokinetic equations and employ a two-pole Landau closure to close the system. Two scenarios have been modelled, highlighting the impact of trapped and passing population, owing to the presence of both NBI Deuterium and minority H for ICRH in the plasma. The first nonlinear simulation focuses on a regime composed of trapped Hydrogen and alpha particles, while the second simulation investigates the dynamics of passing Hydrogen. For the two simulations, we set the magnetic field at the magnetic axis to B 0 = 2.96 T, the major radius is R 0 = 2.845 m, the minor radius is a = 1.14, the temperature of the energetic particles at the magnetic axis is set to T EP = 1000 keV, and the the Lundquist number is S = 10 7 . Furthermore, finite Larmor radius effects are considered for both thermal ions and energetic particles. The magnetic equilibrium used for these analyses has been computed using the VMEC code applied to the JET discharge 99896.

In the first simulation involving trapped hydrogen and alpha particles, we set β EP = 0.4 and β α = 0.001 for trapped hydrogen and alpha particles, respectively. This large β value of trapped energetic hydrogen primarily results from the temperature of the particles rather than their density (n EP = 0.007 × 10 -20 m -3 ), which is 60 times smaller than that of the thermal plasma. The dominant modes in this simulation have been identified as fishbones excited by the trapped population, characterized by toroidal mode number n = 1 family and rather low frequencies (f ∼ 40 kHz). Additionally, during the nonlinear phase, modes such as 1/1, 2/2, 3/3, and 4/4 contributed to the overall dynamics. The electromagnetic perturbation resulting from this first simulation is observed to be located at the inner region of the tokamak, as can be seen in the first two panels of Fig. 1, which shows the poloidal cross sections of the magnetic (first panel) and electrostatic (second panel) potentials at the saturated phase. A clear m = 1 structure is evidenced.

In the second simulation, which focused on studying the dynamics in the presence of passing population, we set β EP s = 0.3. In this case, the dominant Toroidicity-induced Alfvé Eigenmodes (TAEs) corresponding to the n = 3 family were observed during the linear and saturation phases of the simulation. The electromagnetic perturbation during the linear phase is represented in the last two panels of Fig. 1, which shows the poloidal cross sections of the magnetic (third panel) and electrostatic (fourth panel) potentials.

FIG. 1. Snapshots of the poloidal cross sections of the electrostatic and magnetic potentials for the fishbone driven by the trapped population (first two panels) showing the m = 1 structure and for the Alfvén mode driven by the passing population (last two panels).

OVERVIEW OF THE NEW FULL-ORBIT TOROIDAL ACCELERATED PARTICLE SIMULATOR (TAPAS)

The recently developed Toroidal Accelerated PArticle Simulator (TAPAS) has been significantly upgraded since its first version [5] to include a more realistic description of particles in toroidal fusion devices. It has in particular been extended to a full-orbit version, which is especially important for the physics of highly energetic particles like fusion-born alpha particles. The integration of trajectories is performed in Cartesian coordinates in the 6D phase-space (x, y, z, v x , v y , v z ) to facilitate the implementation of the Boris algorithm [START_REF] Boris | Proc. Fourth Conf. Num. Sim. Plasmas[END_REF]. In addition, with respect to the initial version of TAPAS, the code integrates now the trajectories in arbitrary magnetic equilibria that can be given to the code from a numerical file containing the magnetic surfaces and the contravariant components of the equilibrium magnetic field. Therefore, magnetic equilibria built using codes like VMEC [START_REF] Hirshman | [END_REF], SIESTA [8,9] or DESC [10] can be given to TAPAS. The trajectories can be integrated also in the presence of arbitrary 3D electromagnetic fields that can be either analytical or numerical from external codes in generalized coordinates. Since the trajectory integration is done in Cartesian coordinates, TAPAS includes a dedicated module for coordinate transformation from generalized to Cartesian coordinates. The interpolation of the 3D electromagnetic field at the position of the particles is done by means of 3D BSplines. TAPAS has been accelerated on GPUs using a hybrid parallelization based on the MPI-OpenACC paradigm. Lagrange interpolation is employed for 1D or 2D quantities. However, cubic BSplines are used instead for 3D quantities. Moreover, both BSplines and the different diagnostics have been conveniently accelerated on GPU to ensure the optimization of the code. The results of TAPAS are written using the parallel HDF5 library. Special emphasis has been put on the integration of trajectories for particles in the neighbourhood of the last magnetic surface. Also, trajectories that approach the magnetic axis can suffer from numerical instabilities due to possible problems during the magnetic equilibrium reconstruction. For those cases, second-order (resp. third-order) Taylor expansion of the 2D (resp. 3D) magnetic equilibrium is performed. TAPAS handles the initialization of particles in real space using toroidal coordinates (r, θ, ϕ). As for the initialization in velocity space, the flexibility of TAPAS allows using different coordinates. The initialization can be done either in 6D, in which case the velocities are initialized using the Cartesian components (v x , v y , v z ), or in 5D, in which case the gyro-phase ϕ c is randomly sampled from a uniform distribution U ]0,2π] (ϕ c ) and the parallel and perpendicular velocities are selected by initializing the particles in (a) v , µ , or in (b) (E, Λ), or in (c) (E, λ), or in (d) (E, P ϕ ). Here, v is the velocity parallel to the equilibrium magnetic field, µ is the magnetic moment, E is the kinetic energy, λ = v /v is the pitch angle, Λ = µB 0 /E and P ϕ is the toroidal canonical momentum. When using initializations (b), (c) or (d), TAPAS applies the required transformations to get the velocity coordinates in terms of v and µ. Where in the phase-space particles are initialized depends strongly on the analysis to be performed. In that sense, the initial positions of particles can be specifically selected, for instance using one single energy at a given radial position. This allows total control on the initialization. More realistic initialization can be achieved by sampling a target distribution function. This is done by means of a Metropolis-Hastings algorithm [11], based on Markov Chain Monte Carlo (MCMC) method. Finally, collisions of particles on a background Maxwellian (composed of both ions and electrons) are introduced in TAPAS using a combination of deterministic and stochastic operators, representing the Coulomb drag and the diffusion, respectively. More details on the new full-orbit TAPAS will be provided in a forthcoming publication [12].

TAPAS SIMULATIONS OF FUSION-BORN ALPHA PARTICLES WITH MHD ACTIVITY

Initialization and prompt losses

Alpha particles are initialized in the inner core of the tokamak, where the main activity occurs, uniformly in radius (0 < ρ = r/a < 0.25), poloidal angle (0 < θ < 2π) and pitch angle (-1 < λ < 1), but monoenergetic. Different energies (340 keV, 680 keV, 1 MeV and 1.4 MeV) are chosen to account for the effect of the MHD instabilities depending on the energies of alpha particles. For each of these energies, the number of initialized particles is N part ∼ 10 6 . The perturbation from FAR3d is introduced once the system reaches a statistical steady-state in the sense of prompt losses and redistribution of particles in the tokamak. Indeed, for highly energetic particles, prompt losses (or first orbit losses) can be significant due to the large orbit width of trajectories. Also, particles initialized in the inner region explore regions in the tokamak far from the place where they were initialized. In particular, in our case, the perturbation from FAR3d is introduced after t/τ A = 400. The left panel of Fig. 2 shows the time evolution of the fraction of lost particles, measured as f lost, prompt = N lost /N total , for the different energies considered. It is observed that the prompt losses increase with the energy, owing to the dependence of the orbit width on the energy of particles. Also, the steady-state is reached faster for higher energies. The right panel of Fig. 2 represents the fraction of lost particles (prompt losses) at t/τ A = 400 (when the steady-state is reached) as a function of the initial pitch angle. For relatively low energies, the prompt losses are mainly localized around IAEA-CN-2269 λ = -0.4. Increasing the energy results in a wider region in pitch angle where prompt losses occur, but in general the losses occur mainly for λ < 0.5. As a result, a strongly anisotropic distribution is formed.

FIG. 2. Fraction of lost particles during the first orbit (prompt losses) as a function of time for different energies (left).

For the steady-state regime, before introducing the electromagnetic perturbation, fraction of promptly lost particles as a function of their initial pitch angle and for the different energies considered in the paper (right). The legend for both panels is the same.

Transport and losses in the presence of fishbones driven by trapped population

Once the statistically steady-state after the prompt losses is reached, we switch on the perturbation from FAR3d characterizing a fishbone excited by trapped Hydrogen. The fraction of lost particles is measured taking as a reference the state of the system at t/τ A = 400, i.e. we quantify the losses of alpha particles with respect to the number of particles confined in the tokamak after the prompt losses. The quantity of interest is therefore

f lost = N lost -N lost, prompt N total -N lost, prompt
, where N lost is the total number of lost particles as a function of time, which includes also the prompt losses.. Fig. 3 illustrates the impact of the fishbone instability on the confinement of alpha particles. The left (resp. right) panel represents the effect when only the electrostatic (resp. magnetic) component of the instability is introduced in TAPAS. The figure provides the fraction of lost particles for the different energies considered in the paper. It is observed that for relatively low energies, the impact of the electrostatic component is significantly more pronounced than that of the magnetic component. However, when increasing the energy of alpha particles, the impact of the magnetic component becomes comparable to that of the electrostatic component. There is evidence that the fishbone instability that is mainly located in the core region of the tokamak can have deleterious impact on the confinement of alpha particles, leading to up to 25 -30% of the fraction of particles that is lost for energies of the order of 1 MeV or larger. It is to be reminded that this fraction is calculated with respect to the population that remains confined after the prompt losses. Of course, further analysis is required to estimate the nature of the transport (with respect to the diffusive transport), but this is beyond the scope of the present paper. In the remainder of this subsection, both electrostatic and magnetic components are included to account for the total effect of the instability. Although the alpha particles are initialized in the inner region, their large orbit widths make them explore larger radial positions. As a result, the position of the alpha particles and their distribution in space (radially and poloidally) depend strongly on their energy and pitch angle. To illustrate this, the top left panel of Fig. 4 shows the final density of all the particles initialized inside the surface ρ = 0.25 at the energy E = 1.4 MeV (for the sake of clarity only one energy is considered for the top panels of this figure). The color represents the density in a.u. Depending on the pitch angle of the particles, they are mainly localized in the high field side (HFS) for λ < 0 or in the low field side (LFS) for λ > 0. This implies that in the presence of a perturbation leading to losses of particles, those with λ < 0 will be lost in the HFS mid-plane, whereas particles with λ > 0 will be lost in the LFS mid-plane. This is corroborated by the probability density function (PDF) of the poloidal angle of lost particles for positive and negative pitch angles, as illustrated in the top right panel of Fig. 4. The overall radial impact of the fishbone instability can be observed in the four bottom panels of Fig. 4 for the different energies considered. The curves indicate the number of particles (all pith angles included) as a function of the normalized minor radius. The grey areas represent the profiles once the prompt losses have occurred and the red areas represent the final radial distribution of particles. It is observed that the effect of the fishbone is global, although the mode remains localized in the inner region of the tokamak. This global effect is likely due to the large orbit width of alpha particles. Also, the effect seems to be more pronounced when increasing the energy.

IAEA-CN-2269

For the considered initialization of particles, analysis of the pitch angle is provided in Fig. 5, where the PDFs of the pitch angle for the confined (left) and lost (right) particles are plotted. The different energies are indicated using the same conveniton as in the previous figures of the paper. It is to be noted that the right panel of the figure represents the PDF of the pitch angle of the particles that are lost only due to the fishbone instability, i.e. we do not consider for the computation of the PDF the particles that are pormptly lost. Several comments can be made based on these figures. The first obvious observation is that the pitch angle has a significant impact on the confinement and losses of the particles. For low energies, particles with positive and negative pitch angles remain roughly equally confined. When the energy is increased, particles with positive pitch angles tend to be better confined than those with negative pitch angles. This is also reflected in the right panel of Fig. 5. Indeed, it is observed that the PDF of lost particles for negative pitch angles increases with the energy. Finally, whereas the PDF of pitch angle for lost particles extends from λ = -1 up to λ = -0.5, that of positive pitch angles is mostly localized around λ ≈ 0.5. The next analysis concerns the distribution of the energy of confined and lost particles. Let us remind that the particles are monoenergetic in our TAPAS simulations. Fig. 6 represents the PDFs of kinetic energy for the different classes of particles considered in the paper, making the distinction between confined and lost (only due to the perturbation, no prompt losses are considered here, which would introduce a dominant peak in the PDFs of lost particles). Several comments can be made. First, the initially monoenergetic alpha particles remain almost monoenergetic, with variations in the range of 4 -14%. It is interesting to realize that the PDF for confined particles with high energy could be approximated by a Gaussian. This is clearly not the case for relatively low energies. Regarding the PDF for lost particles, they are close to those for confined particles only for intermediate energies E ≈ 1 MeV. For low energies (E < 1 MeV) the PDF are clearly asymmetric, with a more pronounced tail towards low energies. FIG. 6. PDF of the energy for the confined (thick curves)) and lost (thin curves) particles for the different energies considered in the paper.

Finally, after the detailed previous studies with very specific energies for particles initialized inside ρ = 0.25, one can conduct more realistic analyses by making use of the Metropolis-Hastings algorithm for the initialization of particles. For this purpose, we initialize N part ∼ 3 • 10 7 particles sampling the same distribution function as in the FAR3d simulations, i.e. an equivalent Maxwellian with T = 1 MeV, with an initial radial density profile peaking at ρ = 0 and decreasing towards 0 for ρ > 0.5. We have selected an isotropic distribution, but other types can be envisioned. We have observed that the initially peaked density extends quickly towards larger radial positions due to the large orbit of alpha particles and to the prompt losses, as depicted by the dashed blue line of the left panel of Fig. 7. Once the prompt losses have occurred the fishbone is destabilized and the effect on the density profile is represented by the solid red line. As expected, the impact on the density is over the whole radial positions, more significant in the inner core due to the smaller volume. The effect in phase-space is represented in the right panel of Fig. 7, where we plot in logarithmic scale the difference between the distribution functions before the onset of the fishbone instability and at the end of the simulation. From this analysis no clear resonance is evidenced, which might imply that the losses are not induced by by convective resonant transport. Also, the time trace of the number of lost particles have not revealed any characteristic frequency, implying that the losses are not coherent. Further analysis is required to assess the nature of the alpha particle transport in the presence of fishbones. FIG. 7. Density of alpha particles before the onset of the fishbone instability (dashed blue line) and at the end of the simulation (solid red line) (left). Difference between the final distribution function and the one before the onset of the fishbone instability, in logarithmic scale, as a function of the parallel velocity and the magnetic moment for all radial positions (right).

Transport and losses in the presence of Alfvén Eigenmodes driven by passing population

Similar analysis has been performed for the transport and losses of alpha particles in the presence of the Alfvén modes driven by the passing population. As opposed to the transport and losses induced by the fishbone instability, no significant losses have been observed. The result is summarized in Fig. 8. This is in agreement with experimental observations with the FILD diagnostic. IAEA-CN-2269

CONCLUSIONS

The impact of MHD instabilities driven by energetic particles on the transport and losses of fusion-born alpha particles has been analysed in the framework of the last DT experimental campaign at JET. In particular, the discharge 99896 has been modelled using a combination of gyro-fluid simulations performed with FAR3d code and full-orbit trajectory integration using TAPAS code. Special emphasis has been put on the impact of instabilities driven by trapped particles (fishbones) and passing particles (TAE). Significant losses in the presence of fishbone activity has been observed, mainly due to the losses of co-and counter-passing alpha particles near the equatorial plane at the HFS (λ < 0) and at the LFS (λ > 0). Analysis of the distribution function in velocity space does not reveal any signficant resonance, suggesting that the losses might not be due to any convective resonant transport. Furthermore, the losses in the presence of higher frequency Alfvén modes have been observed to be negligible, in agreement with experimental observations. Further analyses need to be performed to take into account the effect of collisions. Moreover, in-depth studies of the nature of the transport of alpha particles together with reduced models must be conducted.

FIG. 3 .

 3 FIG. 3. Fraction of lost particles as a function of time in the presence of the electrostatic (left) or magnetic (right) components of the fishbone mode excited by trapped Hydrogen. The curves are plotted for the different energies of alpha particles considered in the paper.

FIG. 5 .

 5 FIG. 5. PDF of the pitch angle for the confined (left) and lost (right) particles for the different energies considered in the paper.

FIG. 8 .

 8 FIG. 8. Fraction of lost particles as a function of time in the presence of the Alfvén activity driven by passing particles including both electrostatic and magnetic components.

ACKNOWLEDGEMENTS

This work has been carried out within the framework of the EUROfusion Consortium, funded by the European Union via the Euratom Research and Training Programme (Grant Agreement No 101052200 -EUROfusion). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them. This work has received financial support from the AIM4EP project (ANR-21-CE30-0018), funded by the French National Research Agency (ANR), from the Comunidad de Madrid under the project 2019-T1/AMB-13648, and from the Oak Ridge National Laboratory, managed by UT-Battelle, LLC, for the US Department of Energy under Contract No. DE-AC05-00OR22725. TAPAS simulations were performed on HPC resources of IDRIS under the allocations 2021-A0100512455, 2022-AD010512455R1 and 2023-A0140514165 made by GENCI. TAPAS development, optimization and deployment on GPU accelerator were done within the framework of an advanced support program funded by IDRIS and GENCI.


Mar Naranjo-Gomez

Mireia Pelegrin
email: mireia.pelegrin@inserm.fr

Vaccinal effect of HIV-1 antibody therapy: dream or reality?

Keywords: OK mAb-based immunotherapy, vaccinal effect, immunomodulation, adaptive immunity, immune complexes

Purpose of the review:

This review summarizes recent studies reporting the induction of vaccinal effects by HIV-1 antibody therapy. It also puts into perspective preclinical studies that have identified mechanisms involved in the immunomodulatory properties of antiviral antibodies. Finally, it discusses potential therapeutic interventions to enhance host adaptive immune responses in HIV-1 infected patients treated with broadly neutralizing antibodies (bNAbs).

Recent findings:

Recent studies in promising clinical trials have shown that, in addition to controlling viremia, anti-HIV-1 bNAbs are able to enhance the host's humoral and cellular immune response. Such vaccinal effects, in particular the induction of HIV-1-specific CD8 + T-cell responses, have been observed upon treatment with two potent bNAbs (3BNC117 and 10-1074) alone or in combination with latencyreversing agents (LRA). While these studies reinforce the idea that bNAbs can induce protective immunity, the induction of vaccinal effects is not systematic and might depend on both the virological status of the patient as well as the therapeutic strategy chosen.

Summary:

HIV-1 bNAbs can enhance adaptive host immune responses in HIV-1 infected patients. The challenge now is to exploit these immunomodulatory properties to design optimized therapeutic interventions to promote and enhance the induction of protective immunity against HIV-1 infection during bNAbs therapy.

Introduction

Monoclonal antibodies (mAbs) have become therapeutic tools of choice to combat serious human diseases, such as severe viral infections [START_REF] Mullard | FDA approves 100th monoclonal antibody product[END_REF][START_REF] Sun | Broad neutralizing antibody-based strategies to tackle influenza[END_REF][START_REF] Dibo | Antibody Therapy for the Control of Viral Diseases: An Update[END_REF][START_REF] Corti | Tackling COVID-19 with neutralizing monoclonal antibodies[END_REF][START_REF] Crowe | Human Antibodies for Viral Infections[END_REF][START_REF] Julg | Broadly neutralizing antibodies for HIV-1 prevention and therapy[END_REF]. Today, there are as many as 100 mAbs approved for human use and several hundred in development. Potent broadly neutralizing antibodies (bNAbs) against HIV-1 have been developed over the past decade and several have demonstrated efficacy in controlling viremia in HIV-infected patients, suggesting that bNAbs may become viable therapeutic agents for combating HIV-1 infection (reviewed in [START_REF] Caskey | Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic[END_REF][START_REF] Spencer | Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic[END_REF][START_REF] Walsh | Broadly Neutralizing Antibodies for HIV-1 Prevention[END_REF][START_REF] Mahomed | Clinical Trials of Broadly Neutralizing Monoclonal Antibodies for Human Immunodeficiency Virus Prevention: A Review[END_REF][START_REF] Lee | The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infectionstudy protocol for a two-stage randomised phase II trial[END_REF]) .

The therapeutic efficiency of mAbs is driven by their multiple mechanisms of action that go well beyond their neutralization capacity. In addition to the neutralization of free virions by their Fab fragment, the antiviral effect of mAbs is also achieved via the Fc fragment through interactions with Fc receptors (FcRs) expressed by many cells of the immune system [START_REF] Lu | Beyond binding: antibody effector functions in infectious diseases[END_REF][START_REF] Bruhns | Mouse and human FcR effector functions[END_REF][START_REF] Gogesch | The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies[END_REF]. Importantly, Fc-FcγR interactions are a very versatile system for shaping immune responses [START_REF] Bruhns | Mouse and human FcR effector functions[END_REF][START_REF] Nimmerjahn | Fcgamma receptors as regulators of immune responses[END_REF][START_REF] Delidakis | Improving Antibody Therapeutics by Manipulating the Fc Domain: Immunological and Structural Considerations[END_REF]. On one hand, there are multiple FcgRs, either activating or inhibitory, with different affinities for different IgG isotypes.

On the other hand, FcgRs are differentially expressed in multiple immune cells, each with specific functions. This diversity enables a myriad of immune functions essential for combating invading pathogens through direct elimination of viruses and infected cells, as well as modulating host immune responses in an Fc-dependent manner.

Fc-FcγR interactions can lead to viral clearance through different functional mechanisms [START_REF] Lu | Beyond binding: antibody effector functions in infectious diseases[END_REF][START_REF] Bruhns | Mouse and human FcR effector functions[END_REF][START_REF] Gogesch | The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies[END_REF]. The Fc domain allows antibody-opsonized virions to bind to FcγRs and induce their phagocytosis by cells of the innate immune system. Infected cells can also be eliminated by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cell-mediated cytotoxicity (ADCC) or complementdependent cytotoxicity (CDC). Fc-FcγR interactions can also directly affect viral propagation through other mechanisms, such as antibody-dependent cellular viral inhibition (ADCVI). In addition, upon opsonization of viral targets and formation of immune complexes (ICs), engagement of FcγRs by antiviral mAbs has been shown to have immunomodulatory effects leading to the induction of protective immunity ("vaccinal effect") (reviewed in [START_REF] Pelegrin | Fc-Dependent Immunomodulation Induced by Antiviral Therapeutic Antibodies: New Perspectives for Eliciting Protective Immune Responses[END_REF][START_REF] Pelegrin | Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?[END_REF]). These immunomodulatory effects have been reported in several preclinical models of viral infections. While much attention has been paid to the potential of HIV-1 bNAbs to control viral spread, either by neutralizing virions or eliminating infected cells through Fc-mediated effector functions, their immunomodulatory functions have been much less studied to date. However, recent data from HIV-1 infected patients showing that bNAbs can enhance adaptive immune responses, have reinforced the concept that vaccinal effects can be induced under certain conditions and contribute to protection against the disease.

Vaccinal effect of antiviral mAbs: from preclinical models of viral infection to HIV-1 infected patients

The first evidence of induction of vaccinal effects by antiviral antibodies was reported in the early 2000s. They were reported in preclinical models of retroviral infection in mice [START_REF] Gros | Induction of long-term protective antiviral endogenous immune response by short neutralizing monoclonal antibody treatment[END_REF] and in non-human primates (NHPs) [START_REF] Haigwood | Passive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies[END_REF] (Figure 1). Both studies reported improved long-term humoral responses after treatment with antiviral antibodies (administration of mAbs or polyclonal antibodies, respectively).

Similar observations were later on reported in other preclinical NHP models of henipavirus-and HIV-1 infection [START_REF] Bossart | A neutralizing human monoclonal antibody protects african green monkeys from hendra virus challenge[END_REF][START_REF] Geisbert | Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody[END_REF][START_REF] Ng | Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques[END_REF][START_REF] Jaworski | Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques[END_REF]. Notably, treatment of SHIV-infected infant macaques with polyclonal HIV-1 neutralizing IgG led to neutralizing antibody production that contributed to disease protection [START_REF] Ng | Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques[END_REF][START_REF] Jaworski | Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques[END_REF].

Enhanced T-cell responses were subsequently reported in various experimental settings, including in NHP models of HIV-1 infection (Figure 1) [START_REF] Gros | Endogenous cytotoxic T-cell response contributes to the long-term antiretroviral protection induced by a short period of antibody-based immunotherapy of neonatally infected mice[END_REF][START_REF] Michaud | A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy[END_REF][START_REF] Watkins | An anti-HIV-1 V3 loop antibody fully protects crossclade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV[END_REF][START_REF] Barouch | Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys[END_REF][START_REF] Nishimura | Early antibody therapy can induce long-lasting immunity to SHIV[END_REF][START_REF] Nishimura | Immunotherapy during the acute SHIV infection of macaques confers long-term suppression of viremia[END_REF]. Worthy of note, administration of bNAbs induced Gag-specific CD4 + and CD8 + T cells that showed reduced expression of the exhaustion marker PD-1. This antibody-mediated induction of the HIV-specific CD8 + T-cell response was essential to protect infected macaques, as CD8+ T-cell depletion resulted in viral rebound [START_REF] Nishimura | Early antibody therapy can induce long-lasting immunity to SHIV[END_REF]. These observations were the basis for studying the induction of vaccinal effects in bNAb-treated HIV-1 infected patients.

The vaccinal effect of anti-HIV bNAbs was first described in HIV-1 infected patients by Schoofs et al [START_REF] Schoofs | HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1[END_REF] (Figure 1). This study showed that the administration of the bNAb 3BNC117 to HIV-1 infected individuals elicited host humoral responses in viremic and virally suppressed subjects on antiretroviral therapy (ART). Later, Niessl et al. [START_REF] Niessl | Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity[END_REF] showed that anti-HIV-1 antibody therapy was associated with increased virus-specific T-cell immunity. HIV-1-infected individuals on ART received an infusion of a combination of two anti-HIV-1 bNAbs (3BNC117 and 10-1074) at 0, 3, and 6 weeks, followed by an interruption of antiretroviral therapy (analytical treatment interruption; ATI) 2 days after the first antibody infusion. HIV-1-infected individuals on ART without antibody treatment had stable or decreasing levels of HIV-1-specific CD8 + and CD4+ T-cell responses over time. In contrast, patients treated with bNAbs in the ATI setting had improved virus-specific CD8+ T-cell responses as well as improved CD4+ T-cell responses, which were associated with viral suppression for at least 15 weeks after ATI. More recently, two other studies have also reported the effect of anti-HIV-1 bNAbs on the stimulation of T-cell immunity. Rosas-Umbert et al. [33 **] showed that administration of HIV-1 bNAbs at the initiation of ART maintained long-term CD8 + T-cell immunity. They observed that the frequency of Pol-and Gag-specific CD8 + T cells, as well as Gag-induced interferon-γ (IFN-γ) responses, were significantly higher in patients who received adjuvant 3BNC117 therapy than in those who received ART alone. The observed changes in cellular immunity were correlated with the pretreatment sensitivity to 3BNC117. Notably, increased HIV-1-specific immunity was associated with partial or complete virologic control without ART during treatment interruption for up to 4 years. These results suggest that treatment with bNAbs at the time of ART initiation maintains the HIV-1specific CD8 + T-cell responses that are associated with virologic control without ART.

Another clinical trial (phase 1b/2a) in newly diagnosed HIV-1-infected individuals showed that early intervention with the 3BNC117 bNAb, with or without romidepsin (a latency reversal agent, LRA), at ART initiation enhanced plasma HIV-1 RNA decay rates and accelerated the clearance of infected cells compared to ART only [34 **]. Interestingly, early administration of the 3BNC117 bNAb in combination with romidepsin was associated with (i) increased Gag-specific CD8 + T-cell immunity compared with ART alone [START_REF] Gunst | Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial[END_REF] and (ii) sustained ART-free virologic control among persons with 3BNC117-sensitive virus. On the contrary, in an open-label, phase 2a trial including virological suppressed adults infected with HIV-1 and on ART for at least 18 months (NCT02850016), the combination of 3BNC117 bNAb and romidepsin neither significantly affected the latent HIV-1 reservoir nor induced virus-specific CD8 + T-cells responses [START_REF] Gruell | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial[END_REF]. This treatment regime resulted in an unmodified delay in viral rebound during ATI in individuals on long-term ART. These findings support early interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence. However, a two-component clinical trial involving either participants who initiated ART during the acute/early phase of HIV-1 infection (first component) or individuals with viremic control who were naive to ART (second component) reported that bNAb treatment did not alter cellular immune responses. Both groups showed unchanged frequencies of TIGIT + , PD-1 + , CD38 + HLA-DR + and subsets of CD8 + T cells (assessed in peripheral blood mononuclear cells of study participants). Similarly, the level of poly-functional (IFNγ + TNF + MIP-1β + ) HIV-Gag-specific CD8 + T cells remained unchanged despite the early intervention [START_REF] Sneller | Combination anti-HIV antibodies provide sustained virological suppression[END_REF]. Thus, whether and how early treatment is a key parameter to induce vaccinal effects still needs further investigation.

Overall, these observations highlight the potential of HIV-1 bNAbs to stimulate adaptive immune responses under certain treatment regiments. The elucidation of the mechanism involved as well as the identification of immunological, virological and pharmacological factors required to achieve bNAbmediated protective immunity are now key questions with important therapeutic consequences.

Mechanisms involved in the enhancement of adaptive immune responses by antiviral mAbs

Ethical, technical and economic reasons limit the study of the main mechanisms underlying the vaccine effects of mAbs in humans. Thus, this type of research therefore requires relevant experimental models. Although NHPs are extremely useful to assess the protective effects of anti-HIV mAbs [START_REF] Hessell | Passive and active antibody studies in primates to inform HIV vaccines[END_REF][START_REF] Hessell | Animal models in HIV-1 protection and therapy[END_REF], their use in the study of host immunity is limited by technical and cost considerations.

In contrast, infection systems in mice offer many immunological tools and have allowed the dissection of several molecular and cellular mechanisms involved in the enhancement of host immune responses by antiviral mAbs (reviewed [START_REF] Pelegrin | Fc-Dependent Immunomodulation Induced by Antiviral Therapeutic Antibodies: New Perspectives for Eliciting Protective Immune Responses[END_REF][START_REF] Pelegrin | Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?[END_REF]). Using a mouse model of retroviral infection, Pelegrin and colleagues demonstrated that neutralizing antiviral mAbs act as immunomodulatory agents capable of stimulating protective immunity that persists long after the end of treatment (more than 1 year). These studies highlighted the key a role for ICs in enhancing humoral and cellular antiviral response by dendritic cells (DCs) [START_REF] Michaud | A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy[END_REF][START_REF] Lambour | Converting monoclonal antibody-based immunotherapies from passive to active: bringing immune complexes into play[END_REF], neutrophils [START_REF] Naranjo-Gomez | Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies[END_REF], monocytes [START_REF] Lambour | Differential and sequential immunomodulatory role of neutrophils and Ly6Chi inflammatory monocytes during antiviral antibody therapy[END_REF] and natural killer (NK) cells [START_REF] Naranjo-Gomez | Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy[END_REF] in an FcγRs-dependent manner (Figure 2). They also underline that multiple FcγR-expressing cells are involved and cooperate in the induction vaccinal effects by mAbs.

More recently, monocytes and DCs have been shown to play a key role in enhancing CD8 + T cell responses in animal models of acute respiratory viral infections such as SARS-CoV2 and influenza, respectively [START_REF] Bournazos | Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection[END_REF][START_REF] Winkler | Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection[END_REF]. As in the retroviral infection model, this immunomodulatory effect was Fcdependent. During HIV immunotherapy, it has been suggested that the stimulation of the host adaptive immunity is mediated by DC-IC interactions that enhance CD8 + T cell responses, as has been reported in other infectious contexts [START_REF] Michaud | A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy[END_REF][START_REF] Perreau | Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells[END_REF]. However, this hypothesis has not been formally demonstrated and the molecular and cellular mechanisms involved have not been identified. Nevertheless, in support for this hypothesis, several in vitro studies with antibody-opsonized SIV virions have shown that ICs activate DCs leading to increased virus-specific CD4 + T-cell responses [START_REF] Yamamoto | Post-infection immunodeficiency virus control by neutralizing antibodies[END_REF] and enhanced crosspresentation of viral proteins [START_REF] Villinger | Evidence for antibody-mediated enhancement of simian immunodeficiency virus (SIV) Gag antigen processing and cross presentation in SIV-infected rhesus macaques[END_REF]. In sharp contrast, in vitro activation of DCs by HIV-1 virions opsonized with polyclonal IgG showed a decreased capacity to stimulate HIV-1-specific cytotoxic T lymphocytes than free virions [START_REF] Posch | Antibodies attenuate the capacity of dendritic cells to stimulate HIV-specific cytotoxic T lymphocytes[END_REF]. However, it is important to note that the polyclonal nature of the IgG used in this study, whose neutralizing capacity was not characterized, may have had an impact on the results observed. Thus, whether and how DC-IC interactions drive T-cell responses upon bNAbtreatment remains an open question.

The role of ICs in shaping antibody responses against HIV-1 has been described in vaccine approaches based on immunization of mice with ICs formed with recombinant HIV-1 envelope gp120 proteins and anti-gp120 mAbs or polyclonal antibodies from HIV-1-neutralizers. These immunization methods increased serum levels of HIV-1-specific antibodies [START_REF] Hioe | The use of immune complex vaccines to enhance antibody responses against neutralizing epitopes on HIV-1 envelope gp120[END_REF][START_REF] Kumar | Improving immunogenicity of HIV-1 envelope gp120 by glycan removal and immune complex formation[END_REF][START_REF] Kumar | Elicitation of broadly reactive antibodies against glycan-modulated neutralizing V3 epitopes of HIV-1 by immune complex vaccines[END_REF][START_REF] Hioe | Modulation of Antibody Responses to the V1V2 and V3 Regions of HIV-1 Envelope by Immune Complex Vaccines[END_REF][START_REF] Lofano | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement[END_REF]. Mechanistically, modulation of humoral responses occurred via the antigen deposition within B-cell follicles in germinal centers and was dependent on the interaction of ICs with complement receptors (CR), suggesting a role for the complement system in modulating humoral immunity via IC-mediated antigen deposition on follicular dendritic cells (FDC).

How can the vaccinal effect be improved?

Different clinical trials have now shown the immune-enhancing effect of bNAbs, through the potentiation of the humoral [START_REF] Schoofs | HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1[END_REF] and cellular immune response [START_REF] Niessl | Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity[END_REF][START_REF] Rosás-Umbert | Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity[END_REF][START_REF] Gunst | Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial[END_REF]. However, the induction of vaccinal effects is not systematic, as it has not been observed in other clinical trials performed with the same bNAbs [START_REF] Gruell | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial[END_REF][START_REF] Sneller | Combination anti-HIV antibodies provide sustained virological suppression[END_REF]. A better understanding of the immunological, virological and pharmacological factors leading to their induction is thus essential to potentiate them is a wider number of patients.

Bearing in mind the Fc-dependent nature the induction of vaccinal effects and the potential involvement of multiple immune cells, the potentiation of host adaptive immune responses might be achieved by Fc-engineered, gain-of-function bNAbs in combination with personalized host-directed therapies (HDT).

Exploiting Fc-FcγR interactions offers the possibility to improve direct viral propagation control and to enhance vaccinal effects. This could be achieved in several ways. First, Fc-mutations leading to increased affinity for FcγRs expressed in key immune cells are a suitable approach (reviewed in [START_REF] Delidakis | Improving Antibody Therapeutics by Manipulating the Fc Domain: Immunological and Structural Considerations[END_REF][START_REF] Moore | Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions[END_REF][START_REF] Gunn | Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection[END_REF]). Notably, Fc-mutated mAbs against influenza virus showed an improved therapeutic effect that was associated with increased activation of DCs and development of protective CD8 + T-cell responses [START_REF] Bournazos | Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection[END_REF]. These Fc-optimized mAbs included mutations allowing an increased binding to the activating FcγRs, FcγRIIa and FcγRIIIa. Worthy of note, the same mutations included in anti-SARS-CoV2 mAbs were found to have increased binding to both FcγRIIIa alleles (F158 and V158), in contrast to the unmutated Fc variants that display reduced affinity for the F158 allele [START_REF] Cathcart | The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2[END_REF]. These mAbs are currently being tested in clinical trials (NCT04746183). Second, isotype choice and Fcglycoengineering of bNAbs can also alter FcγR and CR binding. In keeping with this, a-fucosylated mAbs have been shown to have enhance effector functions [START_REF] Gunn | Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection[END_REF][START_REF] Moldt | A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcgammaRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques[END_REF] although whether they modulate anti-HIV-1 immune responses has not been addressed to date. In addition, sialylated anti-HIV-1 antibodies used in immunization studies have been shown to enhance humoral responses [START_REF] Lofano | Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement[END_REF] through CR-dependent, IC-mediated antigen deposition on FDC. Third, consideration of FcγR polymorphisms in patients to be treated may represent an asset for improving mAb-based therapies. This is an important issue because several FcγR polymorphisms have been associated with HIV-1 disease progression and vaccine protection [START_REF] Cocklin | The role of Fc receptors in HIV infection and vaccine efficacy[END_REF]. Thus, FcγR polymorphisms can therefore be used as a predictive factor. In addition, Fc-engineering might also help to overcome decreased binding of bNAs to specific FcγR alleles, as above mentioned [START_REF] Cathcart | The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2[END_REF].

Combinatorial approaches involving improved bNAbs and HDT may also represent a major asset for inducing vaccinal effects. Given the development of suppressive immune responses and immune dysfunctions associated with HIV-1 infection, combination therapies will most likely need to target different immune players in order to not only potentiate immune responses but also to counteract the immunosuppressive mechanisms associated with HIV-1 infection. It is now a question of identifying the most effective combination, which will certainly depend on the virological and immunological status of the patients as wells as on the treatment regime (i.e. time of ART initiation, ATI, …). One of the approaches currently being evaluated is the use of LRA. Vaccinal effects have been observed in HIV-1 infected patients in clinical trial based on early intervention with bNAbs combined with the LRA romidepsin (a pan-HDACi, histone deacetylase inhibitor) [START_REF] Gunst | Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial[END_REF]. However, the same combination treatment in chronic patients did not improve CD8 + T-cell responses [START_REF] Gruell | Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial[END_REF]. To further exploit this combinatorial approach, it may be necessary to take into account the effect of pan-HDACi on immune cells. For exemple, pan-HDACi have been described to reduce NK cell function, which is not the case Interestingly, the induction of SHIV-specific responses was observed in some animals after GS-986 administration. Notably, after ATI, the frequency of IFNγ + Gag-specific CD4 + and CD8 + T cells was significantly higher than in control individuals [64], suggesting that the dual combination of GS-986 and bNAbs might represent a suitable approach to enhance SHIV-specific T-cell responses. In keeping with this, TLR9 agonists have also been tested for their antiviral effects in HIV-1 infected patients [66] and are currently being tested in combination with bNAbs in a trial (NCT03837756). Further investigations are needed to determine whether and how this dual treatment induce vaccinal effects.

An alternative approach involving immunostimulatory agents would be to use therapeutic combinations with bNAbs and antibodies targeting regulatory receptors on immune cell. This could be based on the use of agonistic antibodies targeting co-stimulatory receptors (i.e. CD40, OX40, GITR, and CD137) [67,68] and/or the administration of immune checkpoint blocking antibodies (ICB) directed against receptors involved in T-cell exhaustion (i.e. PD1, CTLA4, LAG-3, TIM-3 and TIGIT) (reviewed in [69 *]). Several studies have shown the effect of inhibiting the PD-1-PD-1L interaction in enhancing HIV-1-specific CD4 + T and CD8+ cells responses in NHP-models of HIV-1 infection

[70] and in HIV-1-infected patients [START_REF] Guihot | Drastic decrease of the HIV reservoir in a patient treated with nivolumab for lung cancer[END_REF][START_REF] Gay | Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy[END_REF]. Furthermore, PD-1 blockade has also been shown to enhance HIV-1-specific CD4 + T-cell responses [START_REF] Porichis | Responsiveness of HIV-specific CD4 T cells to PD-1 blockade[END_REF] as well as HIV-1-specific immunoglobulin production [START_REF] Cubas | Inadequate T follicular cell help impairs B cell immunity during HIV infection[END_REF]. This underlines the effect of PD-1-directed immunotherapy on the enhancement of humoral immune responses, as has also been recently described in the context of influenza infection [START_REF] Herati | PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine[END_REF]. Similarly, CTLA-4 blocking agents also augment HIV-1 antibody responses, either alone or in combination with OX40 agonistic antibodies [START_REF] Bradley | Immune checkpoint modulation enhances HIV-1 antibody induction[END_REF]. PD1 and TIGIT blockade have also been shown to enhance NK cell function [START_REF] Porichis | Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells[END_REF][START_REF] Holder | TIGIT blockade enhances NK cell activity against autologous HIV-1-infected CD4+ T cells[END_REF]. Finally, the combination of different ICB (i.e. CTLA4, LAG-3 and TIGIT) might also be beneficial in improving anti-HIV immune response [START_REF] Chiu | Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy[END_REF], although potential adverse effects of such a combination cannot be ruled out. These observations suggest that combinatorial approaches may need to not only "step on the gas" but also "take off the brake" to achieve protective immunity. With this in mind, it will be important to determine the effect of therapeutic approaches combining bNAbs and antibodies targeting immune cell regulatory receptors in the enhancement of adaptive immune responses in HIV-1 infected patients.

Overall, different therapeutic interventions seem promising for enhancing adaptive immune responses in HIV-1 infected patients. Due to the multiples HDT available with distinct modes of action, a myriad of potential combinatorial approaches could be considered for this purpose. A key issue will be thus to identify the most appropriate combination, which will most likely need to be tailored according to the patient's virological and immunological status. This will allow the right medicine to be given to the right patient at the right time.

Conclusion

Several clinical trials have now demonstrated that anti-HIV-1 bNAbs can induce vaccinal effects, reinforcing this concept previously described in preclinical models of HIV-1 infections. These recent studies provide insight into potential factors that may be involved in eliciting protective adaptive immune responses in HIV-1 infected patients. In particular, the virological and immunological status of patients seems to be a key issue, as well as the treatment regimen. In this sense, early treatment could be a key parameter to enhance vaccinal effects. Importantly, current clinical trials now include the study of the modulation of innate and adaptive immune responses [START_REF] Lee | The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infectionstudy protocol for a two-stage randomised phase II trial[END_REF]. There is no doubt that the results of these ongoing studies will shed light on the mechanisms involved in enhancing host immune responses and will guide the development of improved immunotherapies. These will certainly be based on Fc-modified mAbs with improved functions and on combinatorial therapeutic approaches.

The challenge now is to identify and exploit the key mechanisms underlying the vaccine effects of bNAbs, which will be essential to design optimal therapeutic interventions. • Improvement of immune-enhancing effects of bnAbs will likely rely on the design of Fcoptimized bNAbs in combinatorial therapeutic approaches involving tailored host-directed therapies None.

  Taken together, these mouse studies highlight several mechanisms involved in antibody-mediated boosting of both T-cell and B-cell responses. They also highlight the complexity of immune players potentially involved, including several Fc-mediated mechanisms and multiple cells expressing FcγRs and CRs. Whether these mechanisms are also involved in immunotherapies based on HIV-1 bNAbs deserves further investigation.

  with selective HDACi, such as Entinostat [59 *]. Interestingly, the use of pan-HDACi in combination with IL-15 reversed the negative effects of the former [59]. In addition, the combination of HDACi with distinct LRA might also be of interest, as they have been shown to variably affect HIV reactivation and susceptibility to NK cell-mediated killing of T cells that exit viral latency [60]. Furthermore, HDACi have also been shown to affect the basic physiologic features of other effector cells such as macrophage, including their phagocytosis capacity [61]. These observations could help to "re-think" the use of these LRA. Toll-like receptors (TLR) agonists are also being used as LRA in combination with bNAbs [62]. The use TLR agonists offers the advantage of activating lymphoid and myeloid cell subsets (i.e. CD4 + T cells, NK cells and monocytes). Three different studies investigated the effect in viral rebound of two different TLR7 agonists (GS-9620 or GS-986) in combination with bNAbs (PGT121 alone or administered together with the N6 bNAb) after ATI in acute or chronically SHIV-infected monkeys [63-65]. All studies reported either a delay or a partial prevention of viral rebound, including in monkeys chronically infected with SHIV [65 *].

Key points: 3 - 5 •

 35 bNAbs can elicit humoral and cellular adaptive immune responses • Immunological, virological, and pharmacological factors are involved in the induction of adaptive immune responses by bNAbs • Identification of mechanisms involved in immune-enhancing effects of bNAbs will allow the design optimal therapeutic interventions.

Figure 1 .

 1 Figure 1. Timeline of discovery of vaccinal effects by antiviral mAbs.

Figure 2 :

 2 Figure 2: Mechanisms involved in the induction of vaccinal effects. Short treatment of retrovirusinfected mice with a mAb induces a long-term protective humoral and cellular immune response. The enhancement of adaptive immunity is associated with the inhibition of immunosuppressive responses. The mechanisms underlying the induction of protective immunity involve multiple FcγR-expressing cells (i.e. DC, monocytes, neutrophils and NK cells) each with specific functions and mechanisms of action. Reprinted from "Mechanisms Involved in the Induction of Vaccinal Effects", created by "M.Pelegrin, M. Naranjo-Gomez and S. Marsile-Medun" using BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates".

  59. Covino DA, Desimio MG, Doria M: Impact of IL-15 and latency reversing agent combinations in the reactivation and NK cell-mediated suppression of the HIV reservoir. Sci Rep 2022, 12:18567. * This article highlights the effect of different inhibitors of histone deacetylases used as latency-reversal agents on NK cell function and reports a therapeutic combination to reactivate NK cells. 60. Covino DA, Desimio MG, Doria M: Combinations of Histone Deacetylase Inhibitors with Distinct Latency Reversing Agents Variably Affect HIV Reactivation and Susceptibility to NK Cell-Mediated Killing of T Cells That Exit Viral Latency. IJMS 2021, 22:6654. 61. Hany L, Turmel M, Barat C, Ouellet M, Tremblay MJ: Impact of latency-reversing agents on human macrophage physiology. Immunity Inflam & Disease 2023, 11. 62. Hvilsom CT, Søgaard OS: TLR-Agonist Mediated Enhancement of Antibody-Dependent Effector Functions as Strategy For an HIV-1 Cure. Front Immunol 2021, 12:704617. 63. Borducchi EN, Liu J, Nkolola JP, Cadena AM, Yu W-H, Fischinger S, Broge T, Abbink P, Mercado NB, Chandrashekar A, et al.: Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 2018, 563:360-364. 64. Hsu DC, Schuetz A, Imerbsin R, Silsorn D, Pegu A, Inthawong D, Sopanaporn J, Visudhiphan P, Chuenarom W, Keawboon B, et al.: TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption. PLoS Pathog 2021, 17:e1009339. 65. Moldt B, Chandrashekar A, Borducchi EN, Nkolola JP, Stephenson H, Nagel M, Hung M, Goldsmith J, Pace CS, Carr B, et al.: HIV envelope antibodies and TLR7 agonist partially prevent viral rebound in chronically SHIV-infected monkeys. PLoS Pathog 2022, 18:e1010467. * This study reports the effect of bNAbs therapy combined with TLR7 agonist on viral control 66. Vibholm LK, Konrad CV, Schleimann MH, Frattari G, Winckelmann A, Klastrup V, Jensen NM, Jensen SS, Schmidt M, Wittig B, et al.: Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals. AIDS 2019, 33:1315-1325. 67. Attanasio J, Wherry EJ: Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity 2016, 44:1052-1068. 68. Mayes PA, Hance KW, Hoos A: The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov 2018, 17:509-527. 69. Gubser C, Chiu C, Lewin SR, Rasmussen TA: Immune checkpoint blockade in HIV. EBioMedicine 2022, 76:103840. * This review extensively reports recent studies involving several immune checkpoint blocking agents in the context of HIV-1 infection 70. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ, et al.: Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 2009, 458:206-10.

Acknowledgements

We are grateful to BioRender for the edition of the figure 2.

Financial support and sponsorship

This work was supported by grants from Sidaction, ANRS and INSERM state funding granted to M. Naranjo-Gomez (U1183NAR). M. Naranjo-Gomez and M. Pelegrin are members of the "MabImprove Labex", a public grant overseen by the French National Research Agency (ANR) as part of the "Investments for the future" program (reference: ANR-10-LABX -53-01) that also supported this work.

Conflict of interest