The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4⁺ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice

The human immunodeficiency virus (HIV) affects millions of people across the world, and has caused over forty million deaths. HIV attacks the immune system, eventually leading to lower levels of immune cells, which prevent the body from fighting infections. One of the early effects of HIV infection is inflammation, an immune process that helps the body remove foreign invaders like viruses. Unfortunately, long term inflammation can lead to serious conditions like cardiovascular disease and cancer.

Doctors manage HIV using a class of drugs known as antiretrovirals. These drugs reduce the amount of virus in the body, but they cannot eliminate it entirely. This is because, in the early days of infection, copies of the virus build up in certain organs and tissues, like the gut, forming viral reservoirs. Antiretroviral drugs cannot reach these reservoirs to eliminate them, making a cure for HIV out of reach. One way to address this problem is to develop a new class of drugs that can stop the virus from forming these reservoirs in the first place.

Amand et al. wanted to see whether they could reduce the amount of viral reservoirs that form in HIV patients by interrupting a process called inflammasome activation, which occurs early after HIV infection. Inflammasomes are viral detectors that play a role in both inflammation and the formation of viral reservoirs. They activate an enzyme called caspase-1, which in turn activates proteins called cytokines. These cytokines go on to stimulate further inflammation.

Amand et al. wanted to see whether a drug called VX-765, which blocks the activity of the caspase-1 enzyme, could reduce inflammation and stop the formation of viral reservoirs. To do this, Amand et al. first ‘humanized’ mice, by populating them with human immune cells, so they could become infected with HIV. They then infected these mice with HIV, and proceeded to treat them with VX-765 two days after infection. The results showed that these mice had fewer viral reservoirs, lower levels of cytokines and higher numbers of immune cells than untreated mice.

The findings of Amand et al. show that targeting inflammasome activation early after infection could be a promising strategy for treating HIV. Indeed, if similar results were obtained in humans, then this technique may be the road towards a cure for this virus. In any case, it is likely that combining drugs like VX765 with antiretrovirals will improve long term outcomes for people with HIV.

Around 38 million people worldwide are living with the human immunodeficiency virus (HIV) and every year, 1. 7million people get newly infected (UNALDS, 2020). Although combined antiretroviral therapy (cART) can suppress viremia and dramatically improved the life expectancy and the clinical outcome of HIV-1 infected patients (Antiretroviral Therapy Cohort Collaboration, 2008), optimal cART treatment is not curative due to the persistence of a lifelong HIV-1 replication competent reservoir (Siliciano et al., 2003). In addition, cART does not fully resolve HIV-associated immune abnormalities including low-grade chronic inflammation, immune activation/dysfunction, and poor CD4⁺ T cell reconstitution (French et al., 2009; Hunt et al., 2003) and imposes a high burden to the health care system due to treatment resistance, adverse events, and high treatment costs. Recent evidence indicates that inflammation drives HIV-1 reservoirs persistence which in turn contributes to inflammation, creating a pathogenic vicious cycle (Klatt et al., 2013). These inflammatory and immune disorders predispose HIV-1 infected patients under cART to non-AIDS age-related comorbid conditions such as cardiovascular diseases, cancer, and neurodegenerative diseases and are predictive of an increased risk of morbidity and mortality (Kuller et al., 2008). Strategies targeting the mechanisms of HIV-induced inflammation are now evaluated to reduce HIV-1 reservoirs, a fundamental requirement to achieve an HIV cure (Massanella et al., 2016).

HIV infection triggers immune activation/dysfunction and inflammation through several mechanisms such as direct effects of viral proteins on immune cells (Rieckmann et al., 1991; Lee et al., 2003; Simmons et al., 2001), persistent production of type I and II interferons driven by activation of toll-like receptors with HIV-1 RNA (Sereti and Altfeld, 2016), fibrosis of lymphoid structure linked to CD4⁺ T cells depletion (Beignon et al., 2005) and mucosal barriers damages associated with microbial translocation (Klatt and Brenchley, 2010; Gordon et al., 2010). Although inflammation can contribute to the early control of HIV infection, immune dysfunction and chronic inflammation can in turn promote viral spread and the replenishment of the reservoir by stimulating the migration of CD4⁺ T cells to sites of viral replication (Klatt and Silvestri, 2012; Hunt et al., 2011), generating new activated target CD4⁺ T cells (Biancotto et al., 2008). This further leads to a reduced ability of the immune system to kill infected cells, and an increased cell-surface expression of immune checkpoints which contributes to the survival of infected cells (Hatano et al., 2013; Chomont et al., 2009). Furthermore, its stimulates latently infected cells to proliferate but also to produce the virus (Chun et al., 1998; Cameron et al., 2010). Altogether, inflammation, poor antiviral immune response, and HIV-1 persistence create a pathogenic cycle. Interfering with mechanisms linking inflammation and HIV-1 persistence could contribute to an HIV cure and the management of inflammation-linked comorbidities. Micci et al., 2015 established the proof of concept that targeting chronic inflammation with IL-21, a potent immunomodulatory cytokine, in ART-treated SIV-infected non-human primates could improve disease prognosis by reducing immune activation and the viral reservoir. To achieve HIV cure, as the viral reservoir is set within few days after infection (Lewis, 2016), early initiation of novel treatment is required to block reservoirs establishment and may protect the immune system (Rutstein et al., 2017).

Inflammasomes plays important roles in innate immunity and inflammation as multiprotein signalling platforms sensing pathogens, danger signals, and regulating cellular functions (Broz and Dixit, 2016). Upon recognition of the microorganism or danger signals, certain Pattern Recognition Receptors (PRRs) recognize the presence of unique microbial components, so-called pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), and recruit a multiprotein signalling platform containing the adapter protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) which induces the proteolytic activation of the procaspase-1 (Broz and Dixit, 2016). Subsequently, active caspase-1 initiates the release of pro-inflammatory cytokines such as IL-1β and IL-18 and the induction of pyroptosis, an highly inflammatory form of cell death. HIV-1 was described to induce the formation and action of an inflammasome in several cell types and models (Doitsh et al., 2014; Biancotto et al., 2007; Ahmad et al., 2002; Song et al., 2006; Wiercinska-Drapalo et al., 2004; Granowitz et al., 1995; Pugliese et al., 2002; Ahmad et al., 2018; Guo et al., 2014; Chattergoon et al., 2014; Pontillo et al., 2012; Pontillo et al., 2013; Walsh et al., 2014; Jakobsen et al., 2013). Levels of IL-1β and IL-18 were found to be elevated in HIV-1 infected individuals (Biancotto et al., 2007; Ahmad et al., 2002; Song et al., 2006) and to induce HIV-1 production (Wiercinska-Drapalo et al., 2004; Granowitz et al., 1995; Pugliese et al., 2002). Ahmad et al. found that a higher proportion of blood monocytes from HIV-1 infected patients were ASC specks positive, a hallmark of inflammasome activation (Ahmad et al., 2018).

In innate immune cells, such as monocytes/macrophages (Guo et al., 2014; Chattergoon et al., 2014), dendritic cells (Pontillo et al., 2012; Pontillo et al., 2013) and microglial cells (Walsh et al., 2014), HIV-1 infection results in the activation of an inflammasome involving the PRR nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing proteins (NLR) family member 3 (NLRP3). Upon activation of NLRP3 inflammasome, pro-IL-1β is processed by activated caspase 1 to form active IL-1β. NLRP3 inflammasome activation requires a priming signal and an activation signal ultimately leading to pro-inflammatory cytokine release and pyroptosis. More specifically, in human monocytes/macrophages, HIV-1 triggers the NLRP3 inflammasome through the detection of HIV-1 RNA by TLRs and the activation of the NF-κB pathway (Jakobsen et al., 2013). Interferon (IFN)-inducible protein 16 (IFI16) and AIM2 are DNA sensor of the AIM2-like receptors (ALRs) family and can form an inflammasome with ASC upon detection of nuclear DNA. IFI16 is also able to sense HIV-1 in macrophages, but it is unknown whether it can activate an inflammasome in such cell type (Jakobsen et al., 2013). Using lymphoid aggregate culture (HLAC) ex vivo systems from fresh human tonsil or spleen tissues, Doitsh et al. revealed how most of CD4⁺ T cells dies during HIV-1 infection (Doitsh et al., 2010). Over 95% of CD4 T cells are non-permissive to HIV-1 infection and accumulates incomplete DNA transcripts in their cytosol. These transcripts are detected by IFI16, a sensor which activates caspase-1, triggers pyroptosis and the release of intracellular content and pro-inflammatory cytokines including IL-1β (Monroe et al., 2014). The role of the inflammasome in early SIV pathogenesis has recently been shown in the impairment of the innate and adaptive immune response (Barouch et al., 2016) thereby facilitating viral replication (Lu et al., 2016).

Altogether, these results strongly suggest that inflammasome activation occurs early during HIV-1 infection, and could be a central mechanism in the early viral escape to the immune system and furthermore, may facilitate the establishment of the pathogenic cycle of HIV-1 reservoirs persistence and inflammation. VX-765, a selective caspase 1 inhibitor, reduces activation and activity of caspase 1 and antagonizes NLRP3 inflammasome assembly and activation in the context of several inflammatory disorders and diseases such as atherosclerosis, sepsis, or alzheimer disease (Jin et al., 2022; Wu et al., 2021; Flores et al., 2020). Therefore, the aim of our study was to investigate the effects of the Caspase-1 inhibitor VX-765 in an humanized mouse model of HIV-1 infection as a therapeutic strategy to reduce HIV-1-induced inflammation and reservoirs establishment.

We showed in the current work, that targeting inflammasome activation early after HIV-1 infection using the caspase-1 inhibitor VX-765 might represent a potential therapeutic strategy to improve CD4⁺ T cell homeostasis, and to reduce viral load and immune activation. Many studies have outlined the implications of inflammasome activation during the acute and chronic phase of HIV-1 infection as recently reviewed by Leal et al., 2020. The activation of inflammasomes in monocytes, macrophages and dendritic cells leads to the release of cytokines and plays an important part in the first line of host defense against HIV-1 (Leal et al., 2020). However, it can also promote viral spread by the recruitment and activation of CD4⁺ T cells (Klatt and Silvestri, 2012; Hunt et al., 2011). Furthermore, the chronic activation of inflammasomes might be a driver of viral reservoir persistence (Biancotto et al., 2008), which in turn can trigger inflammation, creating a pathogenic cycle. Breaking out of this pathogenic cycle could represent an important building block to reduce non-AIDS-related morbidities caused by persisting inflammation during cART (Deeks et al., 2012). To date, despite increased therapeutic interests (Jin et al., 2022; Wu et al., 2021; Flores et al., 2020), no compound targeting the inflammasome has been marketed (Dutartre, 2016). Nevertheless, the caspase 1 inhibitor VX-765 was approved by the Food and Drug Administration for human clinical trials, showed a good safety profile, and represents currently a promising drug to prevent the onset of inflammation in several diseases (Flores et al., 2020).

In this regard, we investigated in a first step whether the humanized mouse model might be a suitable pre-clinical model to evaluate anti-inflammasone therapy through the detailed kinetics of inflammasome activation in tissues from humanized mice. During the early host response to HIV-1 infection in humanized NSG mice, we described a clear bi-phasic activation profile of inflammasome-related genes in bone marrow, lungs, lymph node, and spleen. The rapid inflammasome-related transcriptomic changes indicate an early sensing of HIV-1 infection, before HIV-1 RNA was quantifiable in the tissues and may reflect the host response to the virus challenge. These findings are in agreement with previous studies from HIV-1 infection in humans (Walsh et al., 2014) and SIV infection in rhesus monkeys (Barouch et al., 2016). Interestingly, in the first phase (up to day 3 post-infection), the expression of NLRP3, IL-1β, and IL-18 was significantly upregulated in several organs before viremia was detectable in blood. Of note, in lymph nodes and bone marrow, transcriptomic changes occurred even before detectability of the virus in the respective tissues and despite variable level of human cells engraftment in tissues of humanized mice. The genes induced in the bone marrow included NLRP3, able to respond to a diverse set of stimuli including HIV ssRNA and proteins, the adaptor ASC, bridging NLRs such as NLRP3 to the inflammatory Caspase-1(CASP-1) and the downstream pro-inflammatory cytokines IL-1β and IL-18 indicating the up-regulation of the entire NLRP3 pathway. In the lymp nodes, the induction of an early inflammasome from day 1 and day 3 p.i. on, was evident from the upregulation of the NOD-like receptors NLRP1, NLRP3, AIM2, CASP-1, and IL-1β, indicating an early host response to HIV-1 infection in humanized mice, in agreement with results obtained from the SIV model (Barouch et al., 2016; Lu et al., 2016). After the initial burst we observed a second phase of transcriptomic changes dominated by IFI16 and AIM2 in bone marrow, lymph nodes, and spleen. In response to DNA, IFI16 is able to mediate the induction of IFN-β through the STING pathway (Unterholzner et al., 2010) but it can also form an inflammasome with ASC upon detection of nuclear DNA (Kerur et al., 2011). AIM2 is a cytoplasmic double stranded DNA sensor that can initiate the assembly of the inflammasome (Hornung et al., 2009; Bürckstümmer et al., 2009; Fernandes-Alnemri et al., 2009). Previous reports indicated that IFI16 restricts HIV-1 infection trough STING in macrophages (Jakobsen et al., 2013) but promotes HIV-1 induced CD4⁺ T cells death by pyroptosis and thus may drive HIV-1 pathogenesis (Doitsh et al., 2010; Monroe et al., 2014). Here we show several direct correlations between IFI16 but also AIM2 expression with viral load and the inverse correlations with the percentage of CD4⁺ T cells (Figure 2). These results are reinforced by several correlations obtained between ASC and CASP-1 expression and the percentage of CD4⁺ T cells in the bone marrow, lymph nodes or in the spleen or with viral load for ASC in the bone marrow 24 days post-infection (Figure 2—figure supplement 1). Taken together these data emphasize the dual role of inflammasome at the onset of HIV-1 infection that fights first the virus and then fuels disease progression.

Inflammasome activation by NLRP3 is a tightly regulated process requiring signals in two main steps. First a priming signal which leads to transcription of inflammasome-related genes and secondly, a signal initiating the assembly of the multiprotein complex. As a result, caspase-1 activity promotes the proteolytic cleavage of the pro-inflammatory cytokines IL-1β and IL-18. We report here significant increases of circulating protein levels of IL-18 at day 10 and 24 post-HIV-1 infection (Figure 3) indicating a full blown inflammasome activity in humanized mice. We also found a high systemic burst of several plasma cytokines (IFN-γ, TNF-α, IP-10, and IL-18) in agreement with the charateristic cytokine storm of acute HIV-1 infection in humans. For IL-1β, we did not find a detectable and significant increase of the cytokine in the plasma of HIV-1 infected mice as compared to non-infected mice, in contrast to mRNA expression in all tissues. This discrepancy might be due to the short half-life of the cytokine (Stacey et al., 2009) and the low basal secretion of protein expression in plasma of the mice. In our humanized mice model, we used an improved engraftment protocol with busulfan myeloablation to reach T cell counts sufficient to sustain long-term HIV replication. Increased CD3⁺ T cell engraftment levels were obtained, constituted of around 61% of human CD3⁺ thymocytes, 8% of human monocytes in the bone marrow, and 3% of human myeloid DCs in the spleen, 22 weeks after engraftment of mice (Singh et al., 2012). Since IL-1β is mainly produced by macrophages and macrophage-like cells, it is tempting to speculate that less protein is secreted after HIV infection in this model as compared to other animal models. In addition, the cytokine is active at the low ng/mL range or even the pg/mL range in humans or in mice. This low level of secretion could explain its fast consumption or fast degradation in plasma of the humanized mice. In contrast, a clear accumulation of IL-18 was shown, and a clear correlation was however achieved between the level of circulating IL-18 and HIV-1 pathogenesis (viral load and loss of CD4⁺ T cells, Figure 3). In summary, all these data demonstrate that the humanized mouse model of HIV infection recapitulates the mean features of inflammasome activation and is well adapted to assess anti-inflammasome therapies against HIV-1-induced immune activation.

To explore the potential effects of direct inflammasome inhibition in vivo, we next evaluated the caspase-1 inhibitor VX-765 administrated as early as day 2 post-infection and for 21 consecutive days. Daily administration of VX-765 significantly reduced circulating levels of IL-18 and levels of circulating pro-inflammatory cytokines, preserved slightly CD4 +T cell homeostasis, and lowered plasma viral load and HIV-1 reservoirs in human CD45⁺ immune cells from the spleen. Interestingly, since a low CD4/CD8 T cell ratio is associated with disease progression to AIDS, our results suggest that VX-765 treatment may delay disease progression and preserve CD4⁺ T cell homeostasis. Pyroptotic CD4⁺ T cells in lymphoid organs was shown through in vitro models to release pro-inflammatory cytokines, inducing a local inflammation that further recruits new CD4⁺ T cells to the site of infection. In addition, innate immune cells recruitment and the activation of an NLRP3 inflammasome might enhance the release of pro-inflammatory mediators. This globally enhances HIV-1 replication, thus stimulating the replenishment of the reservoir. It is worthy to note that treatment with VX-765 reduced significantly plasma viral load and the formation of the HIV-1 reservoir in the spleen of humanized mice. This result needs to be further confirmed in central memory and effector memory T cells in a model of HIV-1 latency in humanized mice in combination with cART treatment to explore this potential.

We show here that inflammasome activation in vivo rather takes places in splenic innate immune CD11c⁺ and CD14⁺ cells than in the splenic adaptive CD4⁺ or CD8⁺ T cells or in the bone marrow immune cells indicating that HIV-1 induced inflammasome activation in splenic CD11c⁺ cells may be the principal source of circulating IL-18. When investigating pyroptosis in subsets of splenic caspase-1 activated cells, we did not find any significant increase in cell death in CD4⁺ and CD8⁺ T cells. In addition, we did not detect any effect of VX-765 in caspase-1 activation, suggesting that the small caspase-1 activation observed in these subsets might reflect a background activity and could probably be induced earlier by HIV-1 infection, as proposed by Terahara K et al. who showed interestingly that live caspase 1 cells might rapidly die in humanized mice (Terahara et al., 2021). Our in vivo data did not confirm previous results obtained in vitro only by the group of Doitsh et al., 2010 who proposed pyroptosis as the main mechanism leading to CD4⁺ T cell depletion after HIV-1 infection. We can not exclude that the assay is not sensitive enough in primary human T cells from humanized mice to show pyroptosis or that we did not catch an earlier best time point. In addition, there is no evidence yet that such microenvironment of abortive infected and bystander CD4⁺ T cells can be recapitulated in lymphoid organs of humanized mice where fewer human CD4⁺ T cells remains as compared to human lymphoid organs. This could also explain the minimal effect of VX-765 on CD4 ⁺T cell depletion as compared to previous results obtained in vitro by Doitsh et al., 2014 HIV-1 infection is associated with programmed cell death, and NLRP3 inflammasome-mediated immune T cell depletion was nevertheless shown here by different correlations with the dowstream pathways of NLRP3. Through serial necropsies, Barouch et al. demonstrated that, following SIV infection, early host response at the mucosal portal of entry and early sites of distal virus spread involved a robust expression of components of the inflammasome and TGF-β pathways which impairs both innate and adaptative immunities (Barouch et al., 2016). Other anti-inflammatory strategies aiming at breaking this vicious circle and reducing HIV persistence are currently investigated in several clinical trials, including the anti-inflammatory, anti-fibrotic angiotensin II blocker losartan (phase 2, NCT01852942) and angiotensin II receptor antagonist telmisartan (phase 1, NCT02170246), immunosuppressors with mTOR inhibitory activities such as sirolimus (phase 2, NCT02440789) and everolimus (phase 4, NCT02429869) or the anti-inflammatory janus kinase inhibitor ruxolitinib (phase 2, NCT02475655). Most of these strategies target inflammation during chronic HIV infection. HIV-1-induced massive systemic immune activation was repeatedly linked to poor outcomes during chronic infection such as the increased risk of cardiovascular complications (Ross et al., 2009; Graham et al., 2013). Furthermore, levels of cytokines IP-10 and IL-18 remain elevated in cART patients compared to healthy donors and elite controllers (Côrtes et al., 2018). Therefore, complementary approaches are needed to reduce persisting immune activation under cART; inhibiting early inflamasomme activation might be a very promising approach that could be combined to cART for treating acute HIV infection. During chronic HIV-1 infection under cART therapy, residual viral replication and viral protein expression from defective provirusses is a continuous driver of inflammation and might also trigger inflammasome activation (Klatt and Silvestri, 2012; Hunt et al., 2011; Biancotto et al., 2008). Furthermore, the incapacity of cART to completely restore immune functions and control chronic inflammation promotes immune aging and the emergence of non-AIDS-related diseases such as cancer, cardiovascular diseases, viral infections, and cognitive decline (Deeks et al., 2012). Although cART reduce the aberrant cytokine production of monocytes, some inflammatory monocytes subsist while phagocytic monocytes decrease, resulting in a lower antigen presentation to CD8⁺ T cells (Novelli et al., 2020). Taken together, all these data suggest that inflamasomme inhibition, by offering simultaneous reduction of inflammation and affecting HIV-1 replication, might be further evaluated to support cure research.

The data have been uploaded in the Zenodo repository.

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Author details

1. Mathieu Amand

   Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Investigation, Methodology, Writing – original draft, Project administration

   Competing interests

   No competing interests declared

2. Philipp Adams

   Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg

   Contribution

   Conceptualization, Resources, Formal analysis, Investigation, Writing – original draft

   Competing interests

   No competing interests declared

3. Rafaela Schober

   Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg

   Contribution

   Resources, Data curation, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

4. Gilles Iserentant

   Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg

   Contribution

   Resources, Formal analysis, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

5. Jean-Yves Servais

   Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg

   Contribution

   Resources, Formal analysis, Writing - review and editing

   Competing interests

   No competing interests declared

6. Michel Moutschen

   Department of Infectious Diseases, University of Liège, CHU de Liège, Liège, Belgium

   Contribution

   Conceptualization, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

7. Carole Seguin-Devaux

   Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing – original draft, Project administration

   For correspondence

   carole.devaux@lih.lu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0636-5222

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