Fc receptors are key discriminatory markers of granulocytes subsets in people living with HIV-1.

Introduction: Granulocytes are innate immune cells that play a key role in pathogen elimination. Recent studies revealed the diversity of granulocytes in terms of phenotype and function. In particular, a subset of granulocytes identified as low-density granulocytes (LDG) has been described in physiological conditions and with increased frequencies in several pathological contexts. However, the properties of LDG are still controversial as they vary according to the pathophysiological environment. Here we investigated the heterogeneity of granulocyte populations and the potential differences in phenotype and immunomodulatory capacity between LDG and normal density granulocytes (NDG) in people living with HIV-1 (PLWH). Methods: To this end, we developed an optimized method to purify LDG and NDG from a single blood sample, and performed in-depth, comparative phenotypic characterization of both granulocyte subtypes. We also assessed the impact of purification steps on the expression of cell surface markers on LDG by immunophenotyping them at different stages of isolation. Results: We identified 9 cell surface markers (CD16, CD32, CD89, CD62L, CD177, CD31, CD10, CXCR4 and CD172α) differentially expressed between LDG and NDG. Noteworthy, markers that distinguish the two subsets include receptors for the Fc part of IgG (CD16, CD32) and IgA (CD89). Importantly, we also highlighted that the purification procedure affects the expression of several cell surface markers (i.e.CD63, CD66b, …) which must be taken into account when characterizing LDG. Our work sheds new light on the properties of LDG in PLWH and provides an extensive characterization of this granulocyte subset in which Fc receptors are key discriminatory markers.

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

PURPOSE OF REVIEW: This review summarizes recent studies reporting the induction of vaccinal effects by human immunodeficiency virus (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 people living with HIV (PLWH) 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 latency-reversing 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 PLWH. 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.

10th antibody industrial symposium: new developments in antibody and adoptive cell therapies.

The annual "Antibody Industrial Symposium", co-organized by LabEx MAbImprove and MabDesign, held its 10th anniversary edition in Montpellier, France, on June 28-29, 2022. The meeting focused on new results and concepts in antibody engineering (naked, mono- or multi-specific, conjugated to drugs or radioelements) and also on new cell-based therapies, such as chimeric antigenic receptor (CAR)-T cells. The symposium, which brought together scientists from academia and industry, also addressed issues concerning the production of these molecules and cells, and the necessary steps to ensure a strong intellectual property protection of these new molecules and approaches. These two days of exchanges allowed a rich discussion among the various actors in the field of therapeutic antibodies.

Fc-Dependent Immunomodulation Induced by Antiviral Therapeutic Antibodies: New Perspectives for Eliciting Protective Immune Responses.

The multiple mechanisms of action of antiviral monoclonal antibodies (mAbs) have made these molecules a potential therapeutic alternative for treating severe viral infections. In addition to their direct effect on viral propagation, several studies have shown that mAbs are able to enhance the host's adaptive immune response and generate long-lasting protective immunity. Such immunomodulatory effects occur in an Fc-dependent manner and rely on Fc-FcγR interactions. It is noteworthy that several FcγR-expressing cells have been shown to play a key role in enhancing humoral and cellular immune responses (so-called "vaccinal effects") in different experimental settings. This review recalls recent findings concerning the vaccinal effects induced by antiviral mAbs, both in several preclinical animal models and in patients treated with mAbs. It summarizes the main cellular and molecular mechanisms involved in these immunomodulatory properties of antiviral mAbs identified in different pathological contexts. It also describes potential therapeutic interventions to enhance host immune responses that could guide the design of improved mAb-based immunotherapies.

Differential and sequential immunomodulatory role of neutrophils and Ly6Chi inflammatory monocytes during antiviral antibody therapy.

Antiviral monoclonal antibodies (mAbs) can generate protective immunity through Fc-FcγRs interactions. We previously showed a role for immune complexes (ICs) in the enhancement of antiviral T-cell responses through FcγR-mediated activation of dendritic cells (DCs). Here we addressed how mAb therapy in retrovirus-infected mice affects the activation of neutrophils and inflammatory monocytes, two FcγR-expressing innate effector cells rapidly recruited to sites of infection. We found that both cell-types activated in vitro by viral ICs secreted chemokines able to recruit monocytes and neutrophils themselves. Moreover, inflammatory cytokines potentiated chemokines and cytokines release by IC-activated cells and induced FcγRIV upregulation. Similarly, infection and mAb-treatment upregulated FcγRIV on neutrophils and inflammatory monocytes and enhanced their cytokines/chemokines secretion. Notably, upon antibody therapy neutrophils and inflammatory monocytes displayed distinct functional activation states and sequentially modulated the antiviral immune response by secreting Th1-type polarizing cytokines and chemokines, which occurred in a FcγRIV-dependent manner. Consistently, FcγRIV- blocking in mAb-treated, infected mice led to reduced immune protection. Our work provides new findings on the immunomodulatory role of neutrophils and monocytes in the enhancement of immune responses upon antiviral mAb therapy.

Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy.

Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.

Vaccinal effect of HIV-1 antibody therapy.

PURPOSE OF REVIEW: The review recalls recent findings regarding the induction of vaccinal effects by HIV-1 broadly neutralizing antibodies (bNAbs) and highlights potential therapeutic strategies to exploit such immunomodulatory properties. RECENT FINDINGS: Studies in different animal models have shown that mAbs can generate long-lasting protective immunity. Induction of this vaccinal effect by HIV-1 bNAbs has also been more recently reported in animal models of HIV-1 infection. Notably, bNAbs treatment of macaques infected with the chimeric simian-human immunodeficiency virus (SHIV) improved both humoral and cellular adaptive immune responses that contributed to disease control. Importantly, this concept has been extended to HIV-1-infected patients as enhancement of humoral responses was recently reported in HIV-1 patients treated with bNAbs. Studies aiming at elucidating the mechanisms underlying these immunomodulatory properties of bNAbs have identified a role for immune complexes in shaping immune responses against HIV-1. They also highlight different Fc (fragment crystallizable) region effector functions that might be required for the enhancement of HIV-1 immune responses upon bNAbs treatment. SUMMARY: HIV-1 bNAbs can elicit protective adaptive immune responses through mechanisms involving multiple cellular and molecular actors of the immune system. Harnessing these mechanisms will be crucial to achieve protective immunity against HIV-1 infection by bNAbs.

[Monoclonal antibodies in infectious diseases: new partners in the therapeutic arsenal]. / Anticorps monoclonaux en infectiologie - Des nouveaux partenaires dans l'arsenal thérapeutique.

Development of therapeutic antibodies for treating infectious diseases is more recent than for cancer and inflammatory diseases. To date, seven antibodies have been approved worldwide and only five in France. Medical indications are so far limited to the prophylaxis of bronchiolitis caused by respiratory syncytial virus (RSV), treatment of multidrug-resistant HIV disease, exposure to rabies and anthrax pulmonary disease, prevention of diarrhea recurrence due to Clostridium difficile, and atypical hemolytic uremic syndrome caused by Escherichia coli. In a near future, new technologies would allow accelerating the development of anti-infectious monoclonal antibodies to improve the anti-bacterial and anti-viral therapeutic arsenal.

TITLE: Anticorps monoclonaux en infectiologie - Des nouveaux partenaires dans l'arsenal thérapeutique. ABSTRACT: Le développement des anticorps thérapeutiques en infectiologie est beaucoup plus récent qu'en cancérologie, à l'exception d'un anticorps anti-virus respiratoire syncytial (VRS), mais il est désormais un domaine en pleine expansion. À l'échelle mondiale, sept de ces anticorps ont déjà été approuvés par des autorités de santé, dont seulement cinq en France. À ce jour, les indications sont restreintes à la prévention de la bronchiolite liée au VRS, au traitement de la maladie VIH/Sida en échec thérapeutique, à l'exposition au virus de la rage et à la maladie du charbon, à la colite post-antibiotique à Clostridium difficile, et au syndrome hémolytique et urémique atypique à Escherichia coli entéro-hémorragique. Dans un futur proche, l'essor des nouvelles technologies devrait permettre d'accélérer le développement d'anticorps monoclonaux anti-infectieux afin d'étoffer l'arsenal antibiotique et antibactérien déjà à disposition. .

Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies.

Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities. However, their immunomodulatory activity during antiviral mAb immunotherapies has never been studied. Our data reveal that neutrophils have an essential role in immunotherapy-induced immune protection of infected mice. Unexpectedly, neutrophils have a limited effect in controlling viral propagation upon passive immunotherapy administration, which is mostly mediated by NK cells. Instead, neutrophils operate as essential inducers of a potent host humoral antiviral response. Thus, neutrophils play an unexpected key role in protective immunity induction by antiviral mAbs. Our work opens approaches to improve antiviral immunotherapies, as it suggests that preserving neutrophil functions and counts might be required for achieving mAb-induced protective immunity.

Converting monoclonal antibody-based immunotherapies from passive to active: bringing immune complexes into play.

Monoclonal antibodies (mAbs), which currently constitute the main class of biotherapeutics, are now recognized as major medical tools that are increasingly being considered to fight severe viral infections. Indeed, the number of antiviral mAbs developed in recent years has grown exponentially. Although their direct effects on viral blunting have been studied in detail, their potential immunomodulatory actions have been overlooked until recently. The ability of antiviral mAbs to modulate antiviral immune responses in infected organisms has recently been revealed. More specifically, upon recognition of their cognate antigens, mAbs form immune complexes (ICs) that can be recognized by the Fc receptors expressed on different immune cells of infected individuals. This binding may be followed by the modulation of the host immune responses. Harnessing this immunomodulatory property may facilitate improvements in the therapeutic potential of antiviral mAbs. This review focuses on the role of ICs formed with different viral determinants and mAbs in the induction of antiviral immune responses in the context of both passive immunotherapies and vaccination strategies. Potential deleterious effects of ICs on the host immune response are also discussed.

Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?

Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems.

The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs.

Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs) are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS)-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies.

Regulatory T cells (Tregs) down-regulate immunity and are associated with chronic viral infections, suggesting that their inhibition might be used to treat life-threatening diseases. Using the FrCasE mouse retroviral model, we have recently shown that short mAb-based immunotherapies can induce life-long protective immunity. This finding has a potentially important therapeutical impact because mAbs are increasingly used to treat severe viral infections. We now report that poor anti-FrCasE immunity in infected mice is due to Treg expansion in secondary lymphoid organs because depletion of Tregs restored humoral and cytotoxic T lymphocyte (CTL) antiviral responses. Kinetic analyses show that Treg expansion is not a consequence of chronicity, but rather is associated with viral spread. Moreover, Treg adoptive transfers indicate that production of the immunosuppressive cytokine IL-10 is essential for preventing a protective immune response. Finally, treatment of infected mice with a virus-neutralizing IgG2a shortly after infection prevents Treg expansion and limits immunosuppressive activity. This effect is rapid, necessary for the development of protective immunity, and depends on mAb effector functions. Therefore, manipulating Tregs may be necessary to confer robust antiviral immunity in the context of mAb-based therapy. This concept likely applies to cancer treatment because vaccine-like effects of mAbs have also been observed in certain cancer immunotherapies.

Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody.

Using FrCas(E) retrovirus-infected newborn mice as a model system, we have shown recently that a long-lasting antiviral immune response essential for healthy survival emerges after a short treatment with a neutralizing (667) IgG2a isotype monoclonal antibody (MAb). This suggested that the mobilization of adaptive immunity by administered MAbs is key for the success in the long term for the MAb-based passive immunotherapy of chronic viral infections. We have addressed here whether the anti-FrCas(E) protective endogenous immunity is the mere consequence of viral propagation blunting, which would simply give time to the immune system to react, and/or to actual immunomodulation by the MAb during the treatment. To this aim, we have compared viral replication, disease progression, and antiviral immune responses between different groups of infected mice: (i) mice treated with either the 667 MAb, its F(ab')(2) fragment, or an IgM (672) with epitopic specificity similar to that of 667 but displaying different effector functions, and (ii) mice receiving no treatment but infected with a low viral inoculum reproducing the initial viral expansion observed in their infected/667 MAb-treated counterparts. Our data show that the reduction of FrCas(E) propagation is insufficient on its own to induce protective immunity and support a direct immunomodulatory action of the 667 MAb. Interestingly, they also point to sequential actions of the administered MAb. In a first step, viral propagation is exclusively controlled by 667 neutralizing activity, and in a second one, this action is complemented by FcgammaR-binding-dependent mechanisms, which most likely combine infected cell cytolysis and the modulation of the antiviral endogenous immune response. Such complementary effects of administered MAbs must be taken into consideration for the improvement of future antiviral MAb-based immunotherapies.

A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy.

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCas(E) murine retrovirus on day 8 after birth die of leukemia within 4-5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through Fc gammaR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies.

An NF-kappaB-dependent role for JunB in the induction of proinflammatory cytokines in LPS-activated bone marrow-derived dendritic cells.

BACKGROUND: Dendritic cells (DCs) play a key role in the induction of adaptive and memory immune responses. Upon encounter with pathogens, they undergo a complex maturation process and migrate toward lymphoid organs where they stimulate immune effector cells. This process is associated with dramatic transcriptome changes, pointing to a paramount role for transcription factors in DC activation and function. The regulation and the role of these transcription factors are however ill-defined and require characterization. Among those, AP-1 is a family of dimeric transcription complexes with an acknowledged role in the control of immunity. However, it has not been studied in detail in DCs yet. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have investigated the regulation and function of one of its essential components, JunB, in primary bone marrow-derived DCs induced to maturate upon stimulation by Escherichia coli lipopolysaccharide (LPS). Our data show fast and transient NF-kappaB-dependent transcriptional induction of the junb gene correlating with the induction of the TNFalpha, IL-6, and IL-12 proinflammatory cytokines. Inhibition of JunB protein induction by RNA interference hampered the transcriptional activation of the TNF-alpha, IL-6, and IL-12p40 genes. Consistently, chromatin immunoprecipitation experiments showed LPS-inducible binding of JunB at AP-1-responsive sites found in promoter regions of these genes. Concomitant LPS-inducible NF-kappaB/p65 binding to these promoters was also observed. CONCLUSIONS/SIGNIFICANCE: We identified a novel role for JunB--that is, induction of proinflammatory cytokines in LPS-activated primary DCs with NF-kappaB acting not only as an inducer of JunB, but also as its transcriptional partner.

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.

Neutralizing monoclonal antibodies (MAbs) are increasingly being considered for blunting human viral infections. However, whether they can also exert indirect effects on endogenous antiviral immune responses has been essentially overlooked. We have recently shown that a short (several-day) period of immunotherapy with the neutralizing 667 MAb of mouse neonates shortly after infection with the lethal FrCas(E) retrovirus not only has an immediate effect on the viral load but also permits an endogenous antiviral immunity to emerge. Even though passive immunotherapy was administered during the particular period of immunocompetence acquisition, the endogenous response eventually arising was protective and persisted long (>1 year) after the MAb has disappeared. As very high levels of anti-FrCas(E) antibodies, predominantly of the immunoglobulin G2a (IgG2a) isotype and showing strong neutralization activity, were found in the sera of MAb-treated mice, it was necessary to address whether this humoral immunity was sufficient on its own to confer full protection against FrCas(E) or whether a cytotoxic T-lymphocyte (CTL) response was also necessary. Using a variety of in vivo assays in young and adult animals previously infected by FrCas(E) and treated by 667, we show here that transient 667 immunotherapy is associated with the emergence of a CTL response against virus-infected cells. This cytotoxic activity is indispensable for long-term antiviral protective immunity, as high neutralizing antibody titers, even enhanced in in vivo CD8(+) cell depletion experiments, cannot prevent the FrCas(E)-induced death of infected/treated mice. Our work may have important therapeutic consequences, as it indicates that a short period of MAb-based immunotherapy conducted at a stage where the immune system is still developing can be associated with the mounting of a functional Th1-type immune response characterized by both CTL and IgG2a-type humoral contributions, the cooperation of which is known to be essential for the containment of chronic infections by a variety of viruses.

Efficient mother-to-child transfer of antiretroviral immunity in the context of preclinical monoclonal antibody-based immunotherapy.

When mice under the age of 5 to 6 days are infected, the FrCas(E) retrovirus induces a neurodegenerative disease leading to death within 1 to 2 months. We have recently reported that transient treatment with a neutralizing monoclonal antibody (MAb) shortly after infection, in addition to an expected immediate decrease in the viral load, also favors the development of a strong protective immune response that persists long after the MAb has been cleared. This observation may have important therapeutic consequences, as it suggests that MAbs might be used, not only as direct neutralizing agents, but also as immunomodulatory agents enabling patients to mount their own antiviral immune responses. We have investigated whether immunoglobulins from mothers who displayed a strong anti-FrCas(E) humoral response induced upon MAb treatment could affect both viremia and the immune systems of FrCas(E)-infected pups till adult age upon placental and/or breastfeeding transfer. The strongest effects, i.e., reduction in the viral load and induction of protective humoral antiviral responses, were observed upon breastfeeding alone and breastfeeding plus placental immunity transfer. However, placental transfer of anti-FrCas(E) antibodies was sufficient to both protect neonatally infected animals and help them initiate a neutralizing anti-FrCas(E) response. Also, administration of a neutralizing MAb to naive mothers during late gestation and breastfeeding could generate similar effects. Taken together, our data support the concept that passive immunotherapies during late gestation and/or breastfeeding might help retrovirally infected neonates prime their own protective immune responses, in addition to exerting an immediate antiviral effect.

Induction of long-term protective antiviral endogenous immune response by short neutralizing monoclonal antibody treatment.

Long-term immune control of viral replication still remains a major challenge in retroviral diseases. Several monoclonal antibodies (MAbs) have already shown antiviral activities in vivo, including in the clinic but their effects on the immune system of treated individuals are essentially unknown. Using the lethal neurodegeneration induced in mice upon infection of neonates by the FrCas(E) retrovirus as a model, we report here that transient treatment by a neutralizing MAb shortly after infection can, after an immediate antiviral effect, favor the development of a strong protective host immune response containing viral propagation long after the MAb has disappeared. In vitro virus neutralization- and complement-mediated cell lysis assays, as well as in vivo viral challenges and serum transfer experiments, indicate a clear and essential contribution of the humoral response to antiviral protection. Our observation may have important therapeutic consequences as it suggests that short antibody-based therapies early after infection should be considered, at least in the case of maternally infected infants, as adjunctive treatment strategies against human immunodeficiency virus, not only for a direct effect on the viral load but also for favoring the emergence of an endogenous antiviral immune response.