# Research Progress on the Relationship between the NLRP3 Inflammasome and Immune Reconstitution in HIV-Infected Patients Receiving Antiretroviral Therapy

Authors: Jinchuan Shi; Zhongdong Zhang; Jie Wu
Journal: Computational and Mathematical Methods in Medicine
 (2022)

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## Abstract

Human immunodeficiency virus (HIV) infection is characterized not only by severe immunodeficiency but also by persistent inflammation and immune activation. These characteristics persist in people living with HIV (PLHIV) receiving effective antiretroviral therapy (ART) and are associated with morbidity and mortality in nonacquired immunodeficiency syndrome (AIDS) events. ART can inhibit HIV replication and promote immune reconstitution, which is currently the most effective way to control AIDS. However, despite effective long-term ART and overall suppression of plasma HIV RNA level, PLHIV still shows chronic low-level inflammation. The exact mechanisms that trigger chronic inflammation are unknown. Activation of the inflammasome is essential for the host response to pathogens, and some recent studies have confirmed the role of the inflammasome in the pathogenesis of inflammatory diseases. The NLRP3 inflammasome has been widely studied, which is a pyrin domain-containing protein 3 belonging to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs). Recent studies suggest that inflammasome-mediated pyroptosis is associated with CD4+ T cell loss in the absence of persistent infectious HIV replication. This article reviews the mechanism of the NLRP3 inflammasome and its correlation with immune reconstitution in PLHIV treated with ART.


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## Body

## 1. Introduction

### 1.1. Possible Mechanism of CD4+ T Cell Depletion Induced by Human Immunodeficiency Virus (HIV)

Over the past 30 years, virologists have been trying to understand how HIV attacks and destroys its main target cells, CD4+ T lymphocytes. The death of these lymphocytes is the root cause of acquired immunodeficiency syndrome (AIDS). What was thought to be the main mechanism of CD4+ T cell depletion is programmed cell death (apoptosis) [1]. Laboratory-adapted HIV strains lead to productive infection and ultimately apoptotic death in CD4+ T cells. However, these activated CD4+ T cells appear to be too limited to explain the substantial loss of CD4+ T cells observed in vivo [2]. Studies have shown that most dying cells in the lymph nodes of infected individuals are bystander CD4+ T cells, but these bystander cells themselves are not infected [3]. Various mechanisms have been proposed to explain the death of these bystander cells, including host factors (e.g., tumor necrosis factor-α, Fas ligand, and TRAIL) [4] and various viral factors released from infected cells (e.g., HIV-1Tat, Vpr, and Nef) [5]. Foreign bodies containing the viral accessory protein Nef released from HIV-infected cells result in bystander CD4+ T cell death in vitro [6]. Also of interest is the role of gp120Env protein in bystander killing [7]. However, not all CD4-expressing cells are rapidly depleted by HIV, such as monocyte-derived macrophages. Instead, monocyte-derived macrophages produce the virus within a few weeks [8], and infected microglia appear to survive for months or even years [9]. These findings suggest that viral infection and replication are not intrinsically linked to cell death. Many retroviruses can infect cells without killing their hosts [10]. Therefore, it is believed that other features of HIV and the interaction between HIV and host contribute to the massive loss of CD4+ T cells in people living with HIV (PLHIV).HIV-associated CD4+ T cell death has been further explored using an ex vivo human lymphoid aggregate culture (HLAC) system formed with fresh human tonsil or spleen tissue. Infection of HLAC with HIV-1 resulted in an almost complete depletion of the CD4+ T cells, but no change in CD8+ T cells. However, only approximately 5% of these CD4+ T cells are effectively infected by the virus [11]. In contrast, 95% of the dying CD4+ T cells are quiescent ones. The cell death observed in HLAC involves abortive viral infection in resting CD4+ T cells, not driven by membrane signaling events via CD4 or chemokine coreceptors nor the elaboration of cytotoxic viral proteins or host factors [12]. Specifically, HIV can bind to and efficiently fuse with these bystander CD4+ T cells. However, due to their quiescent state, the HIV life cycle will be weakened during the chain elongation phase of reverse transcription, leading to incomplete cytoplasmic viral DNA transcripts. Studies regarding how CD4+ T cells die have found that CD4+ T cell depletion is prevented in the presence of a caspase-1 inhibitor. Similarly, shRNA-mediated knockdown of caspase-1 (but not caspase-3 knockdown) prevents the death of HIV-infected CD4+ T cells in HLAC, indicating that caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death, is responsible for the death of these CD4+ T cells abortively infected with HIV [13]. Zhang et al. [14] simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells and found that caspase-1 activation closely correlated with the inflammatory marker expression, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status, and pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.Collectively, the above studies reveal different mechanisms of HIV-induced CD4+ T cells. The toxic effects of HIV-encoded products are not the cause of most cell death. In contrast, death is the result of a strong defensive innate immune response initiated by the host to the virus, leading to “cellular suicide” rather than “viral murder.”


### 1.2. Role of the NLRP3 Inflammasome in Inflammatory Diseases

Pyroptosis is a recently discovered form of programmed cell death induced by microbial infection and endogenous danger signals. Caspase-1/4/5/11-mediated pyroptosis is accompanied by the release of a large number of proinflammatory factors, thus inducing a cascade of amplified inflammatory responses [15]. There are two main molecular mechanisms of pyroptosis: the canonical pathway dependent on caspase-1 and the noncanonical pathway dependent on caspase-4/5/11. Inflammasomes are newly discovered pattern recognition receptors (PRRs) first described in detail in 2002 [16]. Each inflammasome consists of a caspase activation and recruitment domain (CARD) and/or a pyrin protein domain (PYD). A variety of inflammasomes have been identified, including NLRP1, NLRP2, NLRP3, melanoma 2 (AIM2), and NLRC4. Among them, the NLRP3 inflammasome is the most characteristic inflammasome; it is so named because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs), also known as “pyrin domain-containing protein 3” [17]. In addition to the NLRP3 protein, the NLRP3 inflammasome contains apoptosis-associated speckle-like protein (ASC) and procaspase-1 [18]. These three proteins coordinately regulate the function of the NLRP3 inflammasome to ensure immune activity only when appropriate. After activation by inflammatory stimuli, the NLRP3 inflammasome is mainly present in immune and inflammatory cells including macrophages, monocytes, dendritic cells, and splenic neutrophils. Activation of the NLRP3 inflammasome appears to occur in two steps. In the first step, priming signals were triggered, leading to recognition of pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) by toll-like receptor (TLR) and induction of activation of NF-κB-mediated signaling and subsequent upregulation of transcription of inflammasome components, including inactive NLRP3, pro-IL-1β, and pro-IL-18. The second step in inflammasome activation is the oligomerization of NLRP3, which eventually assembles NLRP3, ASC, and procaspase-1 into a complex. The second triggers the conversion of procaspase-1 to caspase-1 and thus activates pro-IL-1β and pro-IL-18 to IL-1β and IL-18 [19].Although innate immune responses are effective in preventing disease and death, inappropriate activation of the NLRP3 inflammasome may lead to progression of various diseases, especially age-related diseases, such as metabolic disorders and metabolic syndrome [20]. Increased production of IL-1β and IL-18 by the NLRP3 inflammasome contributes to plaque progression and instability in atherosclerotic patients and animal models [21]. In macrophages and animal models of type 2 diabetes, hyperglycemia and free fatty acids can also trigger inflammasome activation, ultimately impairing glucose metabolism and enhancing insulin resistance [22]. These findings suggest that accumulation of abnormal metabolites activates the NLRP3 inflammasome during the progression of metabolic diseases. Additionally, NLRP3 inflammasome activation is also associated with various autoimmune and autoinflammatory diseases. For example, NLRP3 inflammasome activation can promote the progression of multiple sclerosis in humans and cause experimental autoimmune encephalomyelitis in animal models [23]. Studies in macrophages and mouse models of colitis have linked aberrant NLRP3 inflammasome activation to inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease [24].CD4+ T cells derived from tissues in PLHIV can naturally cause an inflammatory response, as demonstrated by high levels of cytosolic pro-IL-1β, caspase-1, ASC, and NLRP3 inflammasome [13]. Tan et al. [25] showed that increased inflammatory vesicle activation and upregulation of caspase-1, IL-1β, and NLRP3 levels in up to 25% of HIV/tuberculosis-coinfected patients triggered an excessive inflammatory response after antiretroviral therapy (ART) initiation. Toribio et al. [26] similarly demonstrated that caspase-1 levels were significantly elevated in ART-treated HIV patients compared to controls, which in turn promoted an increase in NLRP3 inflammatory vesicles. CD4+ T cells in pyroptosis releasing proinflammatory cellular inclusions including ATP may provide a second inflammatory stimulus. The stimulus further leads to NLRP3 inflammasome-caused activation of caspase-1 and induces loss of CD4+ T cells [27]. Thus, even if viral replication is reduced by antiretroviral therapy, this “spontaneous inflammation” may still produce sustained pyroptosis, chronic inflammation, and loss of CD4+ T cells.Apoptosis contributes to enhancing defense responses by removing intracellular pathogens and releasing inflammatory cytokines and endogenous danger signals and therefore helps the host to rapidly limit and clear infection. However, in HIV-caused pathogenic inflammation, this beneficial response does not eliminate the main stimulus but turns into a vicious cycle. Specifically, dying CD4+ T cells release inflammatory signals driving “bystander pyroptosis” and attracting more cells into infected lymph nodes to die and eventually produce more inflammation. Pyroptosis is identified as a major mechanism of two characteristic pathogenic events in HIV infection (CD4+ T cell depletion and chronic inflammation); based on this conclusion, HIV infection can be treated through caspase-1. For example, the caspase-1 inhibitor VX-765 is safe and effective in preventing HIV-infected pyroptosis of CD4+ T cells and secretion of IL-1β in HLAC [13]. Coll et al. [28] have found that MCC950, a diaryl sulfonylurea-containing compound, is known to inhibit caspase-1-dependent IL-1β secretion and also inhibits both canonical and noncanonical activation of the NLRP3 inflammasome. MCC950 is shown to suppress NLRP3-induced ASC oligomerization in mouse and human macrophages, reduce IL-1β and IL-18 secretion, and alleviate the severity of encephalomyelitis and cryopyrin-associated periodic syndromes in mouse models. Further studies have shown that MCC950 specifically acts on the NLRP3 inflammasome but not on the NLRP1, AIM2, or NLRC4 inflammasome. These findings raise the possibility of novel “anti-HIV” therapies targeting the host rather than the virus. Such novel anti-HIV therapies, which are aimed at altering host tolerance to the virus rather than inhibiting viral replication, may be particularly beneficial in (1) patients with broad-spectrum resistance or limited access to antiretroviral therapy (ART), (2) blocking the earlier onset of age-related chronic inflammatory diseases that may lead to HIV infection, and (3) acting as a potential treatment of HIV.


### 1.3. Relationship between Chronic Inflammation and Immune Reconstitution in People Living with HIV

Immune activation (IA) [29] and chronic inflammation [30] are currently considered to be responsible for the poor immune reconstitution in PLHIV receiving ART; both of the two factors affect the homeostasis of the T cell repertoire and T lymphocyte counts at the peripheral and thymic levels. ART can reduce systemic inflammation and IA in PLHIV [31], but not allowing cytokine levels in PLHIV to reach normal [32]. IA is characterized by excessive production of inflammatory factors from innate immune cells continuously stimulated by antigens. IA persists even under virological control, but the exact cause of this situation has remained elusive. This persistent inflammation may be caused by a combination of factors, including persistent low-level viral replication [33], coinfection of other chronic viruses, especially cytomegalovirus [34], and poor immune regulation [35]. In addition, the pathogenesis of IA is also associated with other comorbidities, changes in fat distribution, lifestyle, and socioeconomic factors [36].Persistent inflammation is a predictor of clinical events and mortality, which can be improved by ART. The START trial has found that delayed initiation or interruption of ART may increase the levels of some inflammatory factors [37]. In ART-naïve patients, the integrase-strand transfer inhibitor- (INSTI-) based three-drug regimen appears to minimize inflammation compared with the nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based ART regimen [38]. Switching from a ritonavir-boosted protease inhibitor (PI) or NNRTI-based three-drug regimen to an INSTI-based regimen has been shown to have good virological efficacy [39]. Additionally, it seems that different ART regimens have different effects on the CD4/CD8 ratio. Although it has been shown that a two-drug ART regimen reduces the incidence of adverse events, there is also concern that treatment with less than three drugs may lose control of IA. Unfortunately, due to limited studies in this area, further assessment and observation are still needed regarding the impact of two-drug ART regimens on IA and the association between these regimens with specific clinical events.Six months of treatment with an INSTI-based ART regimen can significantly reduce plasma caspase-1 levels in ART-naïve PLHIV [26], and newly initiated ART reduces the percentage of circulating CD4+ T cells expressing caspase-1 [40]. Such studies assess the importance of the specific effects of different treatment regimens on chronic inflammation and IA. Early initiation of INSTI-based regimens markedly decreases the level of plasma caspase-1 and increases indicators of immune recovery such as the CD4/CD8 ratio [41]. Serrano-Villar et al. [42] have also revealed that the CD4/CD8 ratio of INSTI-based ART regimens is higher than that of PI- and NNRTI-based regimens. Existing studies have fully demonstrated that caspase-1 can trigger pyroptosis, which can lead to CD4+ T cell depletion in PLHIV [13]. In turn, destruction of CD4+ T cells by pyroptosis results in further release of inflammatory cytokines to trigger pyrolysis of bystander CD4+ T cells, eventually resulting in a cycle of CD4+ T cell death. Therefore, caspase-1-mediated pyroptosis is a major mechanism of the hallmarks of HIV infection—immunodeficiency and IA [13].


## 1.1. Possible Mechanism of CD4+ T Cell Depletion Induced by Human Immunodeficiency Virus (HIV)

Over the past 30 years, virologists have been trying to understand how HIV attacks and destroys its main target cells, CD4+ T lymphocytes. The death of these lymphocytes is the root cause of acquired immunodeficiency syndrome (AIDS). What was thought to be the main mechanism of CD4+ T cell depletion is programmed cell death (apoptosis) [1]. Laboratory-adapted HIV strains lead to productive infection and ultimately apoptotic death in CD4+ T cells. However, these activated CD4+ T cells appear to be too limited to explain the substantial loss of CD4+ T cells observed in vivo [2]. Studies have shown that most dying cells in the lymph nodes of infected individuals are bystander CD4+ T cells, but these bystander cells themselves are not infected [3]. Various mechanisms have been proposed to explain the death of these bystander cells, including host factors (e.g., tumor necrosis factor-α, Fas ligand, and TRAIL) [4] and various viral factors released from infected cells (e.g., HIV-1Tat, Vpr, and Nef) [5]. Foreign bodies containing the viral accessory protein Nef released from HIV-infected cells result in bystander CD4+ T cell death in vitro [6]. Also of interest is the role of gp120Env protein in bystander killing [7]. However, not all CD4-expressing cells are rapidly depleted by HIV, such as monocyte-derived macrophages. Instead, monocyte-derived macrophages produce the virus within a few weeks [8], and infected microglia appear to survive for months or even years [9]. These findings suggest that viral infection and replication are not intrinsically linked to cell death. Many retroviruses can infect cells without killing their hosts [10]. Therefore, it is believed that other features of HIV and the interaction between HIV and host contribute to the massive loss of CD4+ T cells in people living with HIV (PLHIV).HIV-associated CD4+ T cell death has been further explored using an ex vivo human lymphoid aggregate culture (HLAC) system formed with fresh human tonsil or spleen tissue. Infection of HLAC with HIV-1 resulted in an almost complete depletion of the CD4+ T cells, but no change in CD8+ T cells. However, only approximately 5% of these CD4+ T cells are effectively infected by the virus [11]. In contrast, 95% of the dying CD4+ T cells are quiescent ones. The cell death observed in HLAC involves abortive viral infection in resting CD4+ T cells, not driven by membrane signaling events via CD4 or chemokine coreceptors nor the elaboration of cytotoxic viral proteins or host factors [12]. Specifically, HIV can bind to and efficiently fuse with these bystander CD4+ T cells. However, due to their quiescent state, the HIV life cycle will be weakened during the chain elongation phase of reverse transcription, leading to incomplete cytoplasmic viral DNA transcripts. Studies regarding how CD4+ T cells die have found that CD4+ T cell depletion is prevented in the presence of a caspase-1 inhibitor. Similarly, shRNA-mediated knockdown of caspase-1 (but not caspase-3 knockdown) prevents the death of HIV-infected CD4+ T cells in HLAC, indicating that caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death, is responsible for the death of these CD4+ T cells abortively infected with HIV [13]. Zhang et al. [14] simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells and found that caspase-1 activation closely correlated with the inflammatory marker expression, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status, and pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.Collectively, the above studies reveal different mechanisms of HIV-induced CD4+ T cells. The toxic effects of HIV-encoded products are not the cause of most cell death. In contrast, death is the result of a strong defensive innate immune response initiated by the host to the virus, leading to “cellular suicide” rather than “viral murder.”


## 1.2. Role of the NLRP3 Inflammasome in Inflammatory Diseases

Pyroptosis is a recently discovered form of programmed cell death induced by microbial infection and endogenous danger signals. Caspase-1/4/5/11-mediated pyroptosis is accompanied by the release of a large number of proinflammatory factors, thus inducing a cascade of amplified inflammatory responses [15]. There are two main molecular mechanisms of pyroptosis: the canonical pathway dependent on caspase-1 and the noncanonical pathway dependent on caspase-4/5/11. Inflammasomes are newly discovered pattern recognition receptors (PRRs) first described in detail in 2002 [16]. Each inflammasome consists of a caspase activation and recruitment domain (CARD) and/or a pyrin protein domain (PYD). A variety of inflammasomes have been identified, including NLRP1, NLRP2, NLRP3, melanoma 2 (AIM2), and NLRC4. Among them, the NLRP3 inflammasome is the most characteristic inflammasome; it is so named because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs), also known as “pyrin domain-containing protein 3” [17]. In addition to the NLRP3 protein, the NLRP3 inflammasome contains apoptosis-associated speckle-like protein (ASC) and procaspase-1 [18]. These three proteins coordinately regulate the function of the NLRP3 inflammasome to ensure immune activity only when appropriate. After activation by inflammatory stimuli, the NLRP3 inflammasome is mainly present in immune and inflammatory cells including macrophages, monocytes, dendritic cells, and splenic neutrophils. Activation of the NLRP3 inflammasome appears to occur in two steps. In the first step, priming signals were triggered, leading to recognition of pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) by toll-like receptor (TLR) and induction of activation of NF-κB-mediated signaling and subsequent upregulation of transcription of inflammasome components, including inactive NLRP3, pro-IL-1β, and pro-IL-18. The second step in inflammasome activation is the oligomerization of NLRP3, which eventually assembles NLRP3, ASC, and procaspase-1 into a complex. The second triggers the conversion of procaspase-1 to caspase-1 and thus activates pro-IL-1β and pro-IL-18 to IL-1β and IL-18 [19].Although innate immune responses are effective in preventing disease and death, inappropriate activation of the NLRP3 inflammasome may lead to progression of various diseases, especially age-related diseases, such as metabolic disorders and metabolic syndrome [20]. Increased production of IL-1β and IL-18 by the NLRP3 inflammasome contributes to plaque progression and instability in atherosclerotic patients and animal models [21]. In macrophages and animal models of type 2 diabetes, hyperglycemia and free fatty acids can also trigger inflammasome activation, ultimately impairing glucose metabolism and enhancing insulin resistance [22]. These findings suggest that accumulation of abnormal metabolites activates the NLRP3 inflammasome during the progression of metabolic diseases. Additionally, NLRP3 inflammasome activation is also associated with various autoimmune and autoinflammatory diseases. For example, NLRP3 inflammasome activation can promote the progression of multiple sclerosis in humans and cause experimental autoimmune encephalomyelitis in animal models [23]. Studies in macrophages and mouse models of colitis have linked aberrant NLRP3 inflammasome activation to inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease [24].CD4+ T cells derived from tissues in PLHIV can naturally cause an inflammatory response, as demonstrated by high levels of cytosolic pro-IL-1β, caspase-1, ASC, and NLRP3 inflammasome [13]. Tan et al. [25] showed that increased inflammatory vesicle activation and upregulation of caspase-1, IL-1β, and NLRP3 levels in up to 25% of HIV/tuberculosis-coinfected patients triggered an excessive inflammatory response after antiretroviral therapy (ART) initiation. Toribio et al. [26] similarly demonstrated that caspase-1 levels were significantly elevated in ART-treated HIV patients compared to controls, which in turn promoted an increase in NLRP3 inflammatory vesicles. CD4+ T cells in pyroptosis releasing proinflammatory cellular inclusions including ATP may provide a second inflammatory stimulus. The stimulus further leads to NLRP3 inflammasome-caused activation of caspase-1 and induces loss of CD4+ T cells [27]. Thus, even if viral replication is reduced by antiretroviral therapy, this “spontaneous inflammation” may still produce sustained pyroptosis, chronic inflammation, and loss of CD4+ T cells.Apoptosis contributes to enhancing defense responses by removing intracellular pathogens and releasing inflammatory cytokines and endogenous danger signals and therefore helps the host to rapidly limit and clear infection. However, in HIV-caused pathogenic inflammation, this beneficial response does not eliminate the main stimulus but turns into a vicious cycle. Specifically, dying CD4+ T cells release inflammatory signals driving “bystander pyroptosis” and attracting more cells into infected lymph nodes to die and eventually produce more inflammation. Pyroptosis is identified as a major mechanism of two characteristic pathogenic events in HIV infection (CD4+ T cell depletion and chronic inflammation); based on this conclusion, HIV infection can be treated through caspase-1. For example, the caspase-1 inhibitor VX-765 is safe and effective in preventing HIV-infected pyroptosis of CD4+ T cells and secretion of IL-1β in HLAC [13]. Coll et al. [28] have found that MCC950, a diaryl sulfonylurea-containing compound, is known to inhibit caspase-1-dependent IL-1β secretion and also inhibits both canonical and noncanonical activation of the NLRP3 inflammasome. MCC950 is shown to suppress NLRP3-induced ASC oligomerization in mouse and human macrophages, reduce IL-1β and IL-18 secretion, and alleviate the severity of encephalomyelitis and cryopyrin-associated periodic syndromes in mouse models. Further studies have shown that MCC950 specifically acts on the NLRP3 inflammasome but not on the NLRP1, AIM2, or NLRC4 inflammasome. These findings raise the possibility of novel “anti-HIV” therapies targeting the host rather than the virus. Such novel anti-HIV therapies, which are aimed at altering host tolerance to the virus rather than inhibiting viral replication, may be particularly beneficial in (1) patients with broad-spectrum resistance or limited access to antiretroviral therapy (ART), (2) blocking the earlier onset of age-related chronic inflammatory diseases that may lead to HIV infection, and (3) acting as a potential treatment of HIV.


## 1.3. Relationship between Chronic Inflammation and Immune Reconstitution in People Living with HIV

Immune activation (IA) [29] and chronic inflammation [30] are currently considered to be responsible for the poor immune reconstitution in PLHIV receiving ART; both of the two factors affect the homeostasis of the T cell repertoire and T lymphocyte counts at the peripheral and thymic levels. ART can reduce systemic inflammation and IA in PLHIV [31], but not allowing cytokine levels in PLHIV to reach normal [32]. IA is characterized by excessive production of inflammatory factors from innate immune cells continuously stimulated by antigens. IA persists even under virological control, but the exact cause of this situation has remained elusive. This persistent inflammation may be caused by a combination of factors, including persistent low-level viral replication [33], coinfection of other chronic viruses, especially cytomegalovirus [34], and poor immune regulation [35]. In addition, the pathogenesis of IA is also associated with other comorbidities, changes in fat distribution, lifestyle, and socioeconomic factors [36].Persistent inflammation is a predictor of clinical events and mortality, which can be improved by ART. The START trial has found that delayed initiation or interruption of ART may increase the levels of some inflammatory factors [37]. In ART-naïve patients, the integrase-strand transfer inhibitor- (INSTI-) based three-drug regimen appears to minimize inflammation compared with the nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based ART regimen [38]. Switching from a ritonavir-boosted protease inhibitor (PI) or NNRTI-based three-drug regimen to an INSTI-based regimen has been shown to have good virological efficacy [39]. Additionally, it seems that different ART regimens have different effects on the CD4/CD8 ratio. Although it has been shown that a two-drug ART regimen reduces the incidence of adverse events, there is also concern that treatment with less than three drugs may lose control of IA. Unfortunately, due to limited studies in this area, further assessment and observation are still needed regarding the impact of two-drug ART regimens on IA and the association between these regimens with specific clinical events.Six months of treatment with an INSTI-based ART regimen can significantly reduce plasma caspase-1 levels in ART-naïve PLHIV [26], and newly initiated ART reduces the percentage of circulating CD4+ T cells expressing caspase-1 [40]. Such studies assess the importance of the specific effects of different treatment regimens on chronic inflammation and IA. Early initiation of INSTI-based regimens markedly decreases the level of plasma caspase-1 and increases indicators of immune recovery such as the CD4/CD8 ratio [41]. Serrano-Villar et al. [42] have also revealed that the CD4/CD8 ratio of INSTI-based ART regimens is higher than that of PI- and NNRTI-based regimens. Existing studies have fully demonstrated that caspase-1 can trigger pyroptosis, which can lead to CD4+ T cell depletion in PLHIV [13]. In turn, destruction of CD4+ T cells by pyroptosis results in further release of inflammatory cytokines to trigger pyrolysis of bystander CD4+ T cells, eventually resulting in a cycle of CD4+ T cell death. Therefore, caspase-1-mediated pyroptosis is a major mechanism of the hallmarks of HIV infection—immunodeficiency and IA [13].


## 2. Conclusion

In summary, the host response rather than the virus plays a major role in the pathogenesis of HIV infection; specifically, the host response to viral DNA generated during abortive infection triggers CD4+ T cell death. These findings link the two pathogenic features of HIV infection, namely, CD4+ T cell depletion and chronic inflammation, through a common mechanism, revealing a prominent role of the host in driving HIV pathogenesis. We expect that PLHIV will benefit from a combination of antiviral drugs and other drugs such as caspase-1 inhibitors, which can interrupt pyroptosis. However, current studies have not fully explored whether different ART regimens have consistent effects on IA and inflammation. Given that PLHIV live longer than ever before, it is an urgent task for HIV treatment providers and patients to choose an ART regimen that is most convenient and has the lowest risk of long-term toxicity. Understanding the effects of different ART combinations on IA and systemic inflammation will be the focus of future research.



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*Source: 3179200-2022-03-10.xml*