key: cord-1018227-rctz5f5h authors: Feuillet, Vincent; Canard, Bruno; Trautmann, Alain title: Combining Antivirals and Immunomodulators to Fight COVID-19 date: 2020-11-13 journal: Trends Immunol DOI: 10.1016/j.it.2020.11.003 sha: 005231044be54af2837fc45921b6fd92b04f04df doc_id: 1018227 cord_uid: rctz5f5h The majority of SARS-CoV-2-infected individuals remain paucisymptomatic, contrasting with a minority of infected individuals in danger of death. Here, we speculate that the robust disease resistance of most individuals is due to a swift production of type I interferon (IFNα/β), presumably sufficient to lower the viremia. A minority of infected individuals with a preexisting chronic inflammatory state fail to mount this early efficient response, leading to a delayed harmful inflammatory response. To improve the epidemiological scenario, we propose combining: i) the development of efficient antivirals administered early enough to assist in the production of endogenous IFNα/β; ii) potentiating early IFN responses; iii) administering anti-inflammatory treatments when needed, but not too early to interfere with endogenous antiviral responses. The birth of 'successful' antiviral therapies can be traced back to the fight against Human Immunodeficiency Virus (HIV), which became deeply influential for the Hepatitis C virus (HCV) field and provided a clear start for antiviral discoveries against non-chronic RNA viruses [3] [4] [5] [6] [7] [8] . All antiviral molecules target at least one part of the virus lifecycle, (Figure 2 ), and are classified as early (entry) or late (replication) inhibitors. Antiviral drugs having a viral target are called Direct Acting Antivirals (DAAs), while those having an antiviral effect through host cell proteins are called Indirect Acting Antivirals (IAA). Since the mutation rate of cellular genes is lower than that of viruses, drug resistance is less likely to occur with IAAs [9] . Examples are the pegylated Type I Interferons (IFNs) against HCV, and the CCR5 antagonist maraviroc, targeting HIV-1 entry. None of them are first-line therapeutic choices for HCV or HIV-1-infected patients any longer, though. However, for COVID-19, the efficacy of Type I IFN needs to be evaluated, and a drug targeting SARS-CoV-2 entry is being tested. Indeed, baricitinib, targeting the janus kinase involved in endocytosis of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV2 receptor, is an potential candidate [10] and has shown some activity against COVID-19 in a recent clinical trial (NCT04401579 I ). Accordingly, the TMPRSS2 protease, which also influences ACE2 endocytosis [11] , might also constitute a potential target. Based on HIV-1 and HCV research, an essential effort should be placed on DAAs, which generally target the most conserved viral enzymes: they remain efficacious within a given viral family, and might be tested as broad-spectrum antivirals, even for future outbreaks. There is, for example, a high probability that a nucleoside analog active against SARS-CoV might also work against SARS-CoV-2 and MERS-CoV, given that their RNA-dependent RNA polymerases are structurally and functionally conserved [12] . This may not apply for the Spike protein of SARS-CoV2, be it for vaccine or antiviral design, given that its receptor binding domain sequence differs significantly between coronavirus strains [12, 13] . Discovery of efficient antivirals might be done by proper drug repositioning, i.e. using a drug that is already efficient against another disease, as illustrated by favipiravir. Favipiravir is a purine-base analog which is converted in the cell into a 5'-triphosphate nucleoside analog. Once incorporated into viral RNA, it selectively alters the genetic make-up of Unfortunately, drug repositioning is sometimes attempted without scientific bases. In Box 1 are examples of DAAs, currently repositioned in clinical trials for COVID-19 without solid scientific basis. In Box 2, we discuss the case of hydroxychloroquine (HCQ), a highly controversial anti-viral molecule. In summary, despite their strong need, few sound candidate antivirals have been identified. They include bariticinib, expected to block the entry of SARS-CoV-2 in ACE2-expressing cells, favipiravir and remdesivir which target viral replication. All viruses trigger an antiviral response that relies on the immediate production of IFNβ in the host. [3] [4] [5] [6] [7] [8] . Another mechanism quite likely to occur but never reported so far, is the involvement of Transforming growth factor  For allowing an efficient IFN/β production, one could aim not only at alleviating a TGF-dependent brake, but also at potentiating its production. One such possibility could hypothetically be offered by One main complication of unresolved viral infections can include a cytokine storm that occurs when many leucocytes, mainly macrophages, become over-activated and secrete pro-inflammatory cytokines. The system then triggers an pro-inflammatory programmed cell death [43], affecting mostly macrophages but also lymphocytes; during pyroptosis, the inflammasome of murine macrophages and African green monkey kidney-derived Vero E6 cells have been respectively activated via viroporin 3a and E protein, two SARS-CoV proteins [44, 45] . In addition, in SARS-CoV infected Chinese macaques, binding of SARS-CoV-IgG complexes to monocyte/macrophage Fc receptors promoted inflammasome activation, the subsequent production of a large amount of proinflammatory cytokines in the lungs, and frequent fatal acute lung injury [46] . Twenty years ago, the concept of 'inflammaging' was proposed. It helps to explain the weakness of the immune system in the elderly [47]. One specific aspect of it underlines the importance of Interleukin (IL)-6. The plasma concentrations of IL-6 are low or undetectable in most young individuals and begin increasing in healthy individuals at approximately 50-60 years of age [47] . In the elderly, the plasma concentration of IL-6 is elevated [48] but not that of Tumor Necrosis Factor (TNF) or IL-1β [49, 50] . We posit that Inflammaging might potentially contribute to explaining the predominant susceptibility of the elderly to COVID-19, at least in part [51] . Specifically, several aging-related characteristics have been correlated with most COVID-19 fatalities, generally consisting of individuals older than 70, with a median age of a COVID19-induced death of 80 in Italy [52]. These age-related features concern namely, i) the presence of subclinical systemic inflammation without overt disease, ii) a blunted acquired immune system and IFN/β response, as shown by comparing young and old macaques infected with SARS-CoV [53] and iii) a dramatic reduction of ACE2 expression, demonstrated in old versus young rats relative to uninfected controls [54] . An agingdependent reduction in anti-inflammatory ACE2 activity is likely to worsen SARS-CoV-2 infection outcomes [52]. These possibilities remain conjectural at this point, and the contribution of inflammaging to COVID-19 disease severity will have to be robustly assessed. Altogether, an excessive and prolonged inflammatory response leading to ARDS may underlie the main danger for SARS-CoV-2-infected patients. A major factor favoring its occurrence may be inflammaging, accompanied by elevated and persistent serum pro-inflammatory IL-6 in aged individuals, and by a low expression of ACE2 in the lung of aged animals compared to healthy controls. A variety of approaches to treating a cytokine storm are discussed in Box 3. The link between the kinetics of IFN/β responses and viremia has been established with a mouse-adapted strain of SARS-CoV [55] . In mice infected with a lethal dose of SARS-CoV, an early IFN/β response was clearly beneficial, whereas the inhibition of this early response combined with a late IFN response, was absolutely deleterious, as shown by lung immunopathology, vascular leakage, and suboptimal T cell responses [55] . The efficient response depended on the ability of plasmocytoid DCs to mount an initial IFN/β production in these mice [55] . The lack of beneficial effect of IFN when administered too late, at the ARDS stage, has also been reported in patients infected with MERS-CoV [56] . Similarly, humans that are unable to mount a robust IFN/β response, e.g., due to STAT1 or TYK2 deficiencies, are overly sensitive to a virus such as HSV-1 [57] . At least 10% of 987 patients with life-threatening COVID-19 pneumonia have been reported to harbor neutralizing IgG auto-antibodies against type I IFNs at the onset of the critical disease. These auto-autoantibodies, which neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro, were totally absent in 663 individuals with asymptomatic or mild SARS-CoV-2 infection [58] . If an immune response remains sustained instead of being transient, it may progressively lose its efficacy and be replaced by a harmful inflammatory state. The loss of efficacy results in part from the 'exhaustion' of T cells subjected to chronic stimulation [59] . The inflammatory state might be a consequence of excessive cell-death, due to large tissue damage [60] . Such a hypothesis is based on experimental models, and on human findings, as illustrated below. EBV is an example of a viral infection that is properly controlled in most humans. First, EBV infection leads to a transient intense immune response that lowers viremia and is accompanied by signs of transient inflammation, including fever [61] . This response is usually not followed by persistent inflammation, but in a second phase, viremia is kept under control due to the dynamic process of expansion and contraction of memory CD4 + and CD8 + T cell populations [62, 63] . Thus, the virus is not eradicated, but it is symbiotic with the host. However, in immunocompromised individuals who are unable to mount an intense antiviral response, this virus may become dangerous [64], and can be associated with several malignancies, e.g., endemic Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's lymphoma [65] . An example of an inappropriate antiviral immune response is that occurring upon HIV-1 infection. In this case, the initial antiviral response is usually unable to lower viremia enough to avoid progressive weakening of the adaptive response (in part because activated CD4 + T cells are directly targeted by this virus), and an ensuing chronic inflammatory state. According to our hypothesis, if the initial attack against HIV-1 infection were to be stronger, it might presumably dampen the development of this harmful inflammation. Accordingly, although not a direct J o u r n a l P r e -p r o o f Journal Pre-proof demonstration of this hypothesis, in a study of HIV-1-uninfected young women at high risk of infection who later became infected during follow-up, an early HIV-1-induced cytokine storm was minimized in the subgroup who was given antiretroviral therapy as soon as viral RNA could be detected, and not just after serological tests indicated positivity for the virus [66] . This suggests that an early efficient antiviral treatment might be a solid option for minimizing the cytokine storm. Furthermore, the importance of a biphasic immune response is illustrated by monkeys infected with Simian Immunodeficiency Virus (SIV). The natural hosts, African Green Monkeys, develop a strong but transient IFN/β response following infection, allowing them to control SIV without developing chronic pathology. By contrast, Rhesus Monkeys have shown a sustained IFN/β response to SIV infection, and progressively develop chronic pathology that is similar to AIDS [67, 68] . This suggests that a strong early rise in IFN/β may be key for preventing a delayed, chronic, deleterious IFN/β increase. In another example, bats can be persistently infected with many viruses but rarely display clinical symptoms [69] . A viral infection usually triggers a rapid and significant -but transient -IFN/β response, without evidence of subsequent persistent inflammation [70] . in vitro, macrophages obtained from bats or mice respond differently to stimulation from a TLR3 ligand [70] . Compared to murine macrophages, bat macrophages initially produce more IFN/β, and more IL-10 [70] . If the same is true in vivo, a concept that is potentially ignored, it might lead to an optimal, swift, intense, and transient antiviral response. Of note, bats have developed an efficient antioxidant arsenal [71] . Thus, one might speculate that these different characteristics could help virus-infected bats to better control viremia compared with other mammals and, without developing chronic inflammation. Altogether, a better understanding of the kinetics of antiviral immune responses against different viruses (highlighting successful outcomes) may better inform the development of new putative antiviral treatments. In our view, a rational treatment against SARS-Cov-2 should take into account the disease kinetics summarized in To reduce or impair viral replication, a safe DAA might constitute an interesting option--prophylactically centered around index cases and administered as early as possible following infection. Indeed, a drug capable of curtailing viremia at the beginning of the infection --even modestly --might save a series of complications (e.g. cytokine storms or hemorrhagic fevers, depending on the virus) and lower the case-fatality ratio [72, 73] . To do this, the whole chain of diagnostics must be brought to a higher level of understanding and efficiency, e.g. by providing education about being tested (in the general population via family doctors) and offering accurate/cost-effective tests. We posit that only if accurate diagnostics are optimized in the management of infected patients, can morbidity and mortality be reduced in a viral pandemic. Thus, we argue that the identification and detection of early markers of infection, as well as normalized sampling for qPCR protocols need to become a standard routine. The natural antiviral response, IFN-dependent, is decisive for blocking virus propagation in the infected tissue. We propose that a first option might be to treat virally-infected individuals with IFN/β when a paucisymptomatic disease begins to worsen. Associated with ribavirin, subcutaneous IFNα injections have increased the probability of clearance of HCV [74] and the survival of MERS-infected patients [75] . Moreover, compared to controls, a two-fold reduction in 28-day mortality of severe COVID-19 patients receiving intravenous IFNα injections was recently reported [76] . A second option may be to unleash the endogenous IFN/β response that has been blunted by the virus. Specifically, since TGF is a potent immunosuppressor, and as SARS-CoV can trigger a PLpro-dependent increase of TGF in human promonocytic cells [33], we argue that there may be a strong rationale for unblocking the IFN/β response with inhibitors of the TGF pathway, although this possibility remains to be rigorously investigated. Accordingly, several An anti-TGF approach might also be important for another reason: a chronic inflammatory condition is likely to activate anti-inflammatory mechanisms, including increased TGFconcentrations that are susceptible to block IFN/β signaling. This hypothesis is consistent with the finding that increased serum TGF concentrations have been measured in patients with asthma [79] or diabetes [80] . [82] , and influenza virus-induced murine pneumonia [83] , as well as in a double-blind placebo-controlled trial of asthma treatments [84] . If proven useful, this molecule (already available as oral capsule), might be potentially administered when the first clear symptoms appear, but this possibility also remains to be robustly tested. We suggest that the best approach to preventing the occurrence of a cytokine storm in virally-infected individuals is via an efficient early antiviral treatment. A similar observation was made in the case of hyperacute HIV-1 infection [66] . We propose that the main treatments to be considered upon severe exacerbation of patient symptoms include: i) administering anti-inflammatory molecules: the use of corticosteroid dexamethasone can reduce the mortality of patients with severe COVID-19 [85] . Colchicine is already being used to safely treat certain chronic inflammatory diseases. Another possible approach might be the injection of anakinra, which is a natural antagonist to the receptor for inflammatory molecule IL-1. In a retrospective cohort study, anakinra administration reduced the need for invasive mechanical ventilation, as well as mortality among patients with severe forms of COVID-19, relative to controls [86] ( IX ). ii) Administering neutralizing antibodies against pro-inflammatory cytokines: these days, the most widely-tested antibody is anti-IL6R, but anti-TNF and anti-IL-1 might certainly deserve consideration. iii) Administering high-dose IVIg as a potentially promising treatment. Note that the rationale for this approach -i.e. as an anti-inflammatory agent is entirely distinct from that of administering serum from convalescent patients, in which improving the antiviral response of the patient is the major goal; unfortunately, this approach does not seem to be efficient against SARS-CoV-2 [87]. And iv) We argue that maintaining an antiviral treatment when the inflammatory symptoms increase might be important for limiting virus-induced inflammation. In this Opinion, we have provided arguments in favor of the presented hypothesis to explain the paradox between the low morbidity of SARS-CoV-2 observed in a majority of individuals, and the high morbidity observed in a minority of the global population. The key arguments for our reasoning are the importance of IFN/β and its release kinetics, the HCQ has a clinical recognized efficiency as an antimalarial agent [92, 93] and as an antiinflammatory/immunosuppressor drug --useful in certain inflammatory diseases [94] . In addition, certain HCQ antiviral effects against HIV-1 were demonstrated in vitro 30 years ago [95] . However, its in vitro activity does not translate to comparable concentrations in vivo. This is the case for several viruses in mouse, ferret, hamster and guinea pig models, for influenza [96] , Nipah [97] and Ebola [98] , and in humans for chikungunya [99] and dengue [100] . The direct antiviral effects of HCQ observed in vitro are likely linked to the alkalinization of acid compartments of infected cells. This can interfere with the entry of the virus into the cell (since endocytosis is slowed down by such alkalinization), and/or at a later stage of viral replication [98] . However, in vivo, any potential antiviral effects of HCQ (if an effective concentration is large enough), if at all, are likely to be masked by its immunosuppressive properties, although this remains to be tested. This might explain why HCQ, while efficient in vitro against the Vero cell line infected with SARS-Cov-2, is totally inefficient in preventing infection, or in treating SARS-CoV-2-infected macaques [101] . HCQ has also been reported to be an efficient putative treatment against COVID-19 in a few clinical trials without control groups [102] findings that so far, have not been confirmed in trials with control groups [103] [104] [105] [106] . Therefore, any use of HCQ as a putative treatment/aid of COVID-19 patients remains completely unsubstantiated. The main treatments used to limit the consequences of cytokine storms include administering anti-inflammatory molecules such as glucocorticoids, antibodies neutralizing pro-inflammatory cytokines, and high-dose intravenous immunoglobulin therapy (IVIg). Anti-inflammatory molecules. Since inflammation is an essential component in the establishment of an effective antiviral immune response, anti-inflammatory drugs may constitute an aggravating factor in the initial stages of viral infection [107] . It is thus reasonable to propose that their use should be strictly restricted to the late stage of the cytokine storm. During the pandemics of SARS-CoV and MERS-CoV outbreaks, corticosteroids were not routinely recommended. However, in the case of SARS-CoV2, the use of dexamethasone significantly reduced mortality of patients with severe COVID-19, and is now considered as an FDA-and EMA-(European Medicines Agency) approved treatment for COVID-19 [85] . An interesting alternative to corticosteroids might be colchicine, a safe and low-cost drug, which can inhibit the inflammasome [108] , and is already used to treat several inflammatory diseases such as atherosclerosis [109] , as well as having shown some anti-viral effects against Flaviviridae [110] . Accordingly, colchicine is currently being tested in several clinical trials related to COVID-19 and results are eagerly awaited (NCT04322565 IV , NCT04326790 V , NCT04322682 VI ), the latter foreseeing the inclusion of 6000 participants. and/or direct fusion of cell and viral membranes. The S protein is cleaved by various cellular proteases, e.g., TMPRSS2, into two subunits, S1 and S2 ("priming process"), and at a S2' site upstream to the fusion peptide [13] . The viral genome is translated into two polyproteins which are cleaved by two viral proteases, chymotrypsin-like 3CLpro and papain-like PLpro, to generate a large replication and transcription complex orchestrating genome replication and synthesis of messenger RNAs. New viral genomes recruit viral structural proteins to generate new virions released by exocytosis [6] . Red: potential inhibitors pointing towards their demonstrated targets. A question mark indicates that the target is putative, as discussed in the text. CQ: Chloroquine; HCQ: Hydroxychloroquine. Figure 3 . Kinetics of SARS-CoV2 viral load following infection, in parallel with the IFN/β response, and the evolution of inflammatory cytokines. Top: illustrates the case of most individuals in the population that remain asymptomatic or paucisymptomatic. In these individuals, efficient anti-viral immune responses --characterized by a significant production of IFN/and a limited production of inflammatory cytokines--can lead to virus eradication [1] . Bottom: illustrates the case of patients more severely affected by the virus. These patients show ineffective/delayed production of IFN/, uncontrolled viral load and subsequent overproduction of inflammatory cytokines (cytokine storm) [1] . In the latter case, we propose that antivirals should be administered to patients as soon as possible, and maintained, whereas immunomodulators should be given when the disease worsens because of harmful inflammation. 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Illegitimate drug repositioning The first illegitimate drug repositioning for COVID-19 is the neuraminidase inhibitor oseltamivir, initially used against Influenza viruses. This inhibitor was designed using the crystal structure of the Influenza A N9 neuraminidase [88]. It is the first successful example of structure-based drug design against a virus pathogen. However, since there is no neuraminidase in SARS-CoVs Perhaps public ignorance and confusion is sustaining this illegitimate path. The second example is that of ritonavir or lopinavir. These drugs are HIV protease inhibitors --tested as early as 2004, and found to have an 'apparent favorable effect Later, the effects of these drugs were to be non-existent [90]; yet, they are still being tested in numerous clinical trials that have mobilize research efforts based on a result that is already known to be disappointing Box 2. The case of Hydroxychloroquine (HCQ) Anti-IL6, anti-TNF and anti-IL-1 antibodies have been successfully used to treat several autoimmune inflammatory diseases such rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, and gout [111]. The serum concentration of these cytokines can be found to be abnormally high in severe COVID-19 patients Moreover, the cytokine storm that can be triggered in certain cancer patients upon adoptive transfer of chimeric antigen receptor (CAR)T cells can be controlled in certain situations with anti-IL6/IL6R neutralizing antibodies High-dose IVIg therapy has successfully been used for treating inflammatory autoimmune diseases such as thrombocytopenia purpura [118] or Kawasaki's disease Such therapy in humans has achieved good tolerance and variable clinical benefits in Respiratory Syncytial Virus (RSV) [120], SARS-CoV [121] and dengue virus infections [122]. Its most likely mechanism of action includes inhibition of myeloid cells mediated by the FcRIIB receptor (CD32b), since the effect of IVIg was reported to be completely lost in FcR-deficient mice IVIg has begun its use for severe cases of COVID-19 These three ways of treating cytokine storms (anti-inflammatory molecules, neutralizing monoclonal antibodies and IVIg) -among others -await further consideration in future studies. Outstanding questions Which basic viral properties or targets (e.g. SARS-CoV2) are most likely to allow the development of broad spectrum anti-viral molecules? We thank Cecile Peltekian, Carine Cormary-Feuillet, Guillaume Hoeffel, Ivan & Philippe Ascher for critical reading of the manuscript and for correcting the English language. BC is supported by a grant from the Fondation pour la Recherche Médicale (FRM -Aide aux Equipes). Due to the lack of space, several meaningful papers could not be quoted, and we apologize to the authors for this. Author contributions: All authors contributed equally to the writing of the review. All artwork was done by VF. Competing interests: The authors have no competing interests as defined by Trends in Immunology, or other interests that might be perceived to influence the interpretation of the article. Glossary ACE2: Converts angiotensin I to angiotensin. Expressed in lung, heart, intestine and kidney. ACE2 is the cellular receptor of SARS-CoV and SARS-CoV-2. Dengue virus: RNA virus of the Flaviviridae family, responsible for a mosquito-borne tropical disease (dengue fever). In some cases, the disease may evolve towards dengue hemorrhagic fever, or dengue shock syndrome. Drug repurposing: a drug recognized for its efficacy against a first disease is repurposed when it is used for treating another disease.Exhaustion: state of T cells that have lost most of their efficacy and effector function, after prolonged, chronic stimulation. proportion of disease-induced deaths compared to the total number of people diagnosed with the disease. IFNβ: natural and potent antiviral molecule secreted by most cells of the organism. Binds to its receptor IFNAR, triggering the expression of IFN, which binds to the same receptor with a lower affinity than IFNβ.Indirect Acting Antivirals (IAA): molecules targeting host cell components required for virus replication, thus producing an indirect antiviral effect.Inflammaging: used to describe changes observed in the elderly, appearing as a chronic low-grade inflammation associated with a weakening of immune system efficacy.inflammasome: cytoplasmic complex regulating caspase activation, converting interleukins from inactive to active forms.