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Chan, Y.T.;  Cheong, H.C.;  Tang, T.F.;  Rajasuriar, R.;  Cheng, K.;  Looi, C.Y.;  Wong, W.F.;  Kamarulzaman, A. T Cell Immune Checkpoint Molecules in HIV. Encyclopedia. Available online: https://encyclopedia.pub/entry/33774 (accessed on 20 April 2024).
Chan YT,  Cheong HC,  Tang TF,  Rajasuriar R,  Cheng K,  Looi CY, et al. T Cell Immune Checkpoint Molecules in HIV. Encyclopedia. Available at: https://encyclopedia.pub/entry/33774. Accessed April 20, 2024.
Chan, Yee Teng, Heng Choon Cheong, Ting Fang Tang, Reena Rajasuriar, Kian-Kai Cheng, Chung Yeng Looi, Won Fen Wong, Adeeba Kamarulzaman. "T Cell Immune Checkpoint Molecules in HIV" Encyclopedia, https://encyclopedia.pub/entry/33774 (accessed April 20, 2024).
Chan, Y.T.,  Cheong, H.C.,  Tang, T.F.,  Rajasuriar, R.,  Cheng, K.,  Looi, C.Y.,  Wong, W.F., & Kamarulzaman, A. (2022, November 10). T Cell Immune Checkpoint Molecules in HIV. In Encyclopedia. https://encyclopedia.pub/entry/33774
Chan, Yee Teng, et al. "T Cell Immune Checkpoint Molecules in HIV." Encyclopedia. Web. 10 November, 2022.
T Cell Immune Checkpoint Molecules in HIV
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T cell exhaustion is a condition of cell dysfunction despite antigen engagement, characterized by augmented surface expression of immune checkpoint molecules such as programmed cell death protein 1 (PD-1), which suppress T cell receptor (TCR) signaling and negatively impact the proliferative and effector activities of T cells. T cell function is tightly modulated by cellular glucose metabolism, which produces adequate energy to support a robust reaction when battling pathogen infection. The transition of the T cells from an active to an exhausted state following pathogen persistence involves a drastic change in metabolic activity. The human immunodeficiency virus (HIV) is a human pathogen that attacks the immune system by targeting CD4+ T lymphocytes. HIV infection can result in acquired immunodeficiency syndrome (AIDS), a fatal stage at which the host immune system collapses and becomes vulnerable to many types of opportunistic infections.

CTLA-4 HIV PD-1 TIM-3 LAG-3 TIGIT

1. Introduction

The human immunodeficiency virus (HIV) is a human pathogen that attacks the immune system by targeting CD4+ T lymphocytes. HIV infection can result in acquired immunodeficiency syndrome (AIDS), a fatal stage at which the host immune system collapses and becomes vulnerable to many types of opportunistic infections. There is currently no effective cure or prophylactic vaccine for HIV. However, highly active antiretroviral therapy (HAART), which comprises a combination of at least three antiretroviral regimens of different classes such as nucleoside reverse transcriptase inhibitors (typically tenofovir), non-nucleoside reverse transcriptase inhibitors, or protease inhibitors, has significantly increased the lifespan of people living with HIV (PLWH). Nonetheless, low level of viral replication persists even in aviremic PLWH due to latently infected cells; hence, a lifelong treatment is necessary to prevent HIV rebound. Early HIV infection elicits robust T cell-mediated responses, but such antiviral responses wane as the infection persists. This is caused by a spectrum of functional defects in CD8+ T cells or exhaustion that arises following chronic antigen exposure [1][2].
T cells are the centerpiece in the field of immune checkpoint-based immunotherapy, which is widely applied in clinics nowadays. Immune checkpoint blockade inhibits the negative signal in T cells and thus results in active effector functions, i.e., secretion of cytokines and cytotoxic elimination of target cells. Immune checkpoint-based immunotherapy has been shown to be an effective therapeutic treatment for tumor malignancies, though less so in clinical trials involving infectious diseases such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections, particularly for reviving T cell activity. Studies have reported varying degrees of suboptimal T cell activity and poor durability in a simian immunodeficiency virus (SIV)-infected rhesus macaque model [3], as well as in case reports among PLWH [4]. Most PLWH could only regenerate a limited number of functional T cells below the immuno-threshold, hence the clinical use of immune checkpoint-based immunotherapy remains questionable in the infection setting [5]. This suggests that the immune checkpoint blockade alone might not be adequate to reprogram the chromatin landscape of exhausted T cells, and this necessitates the development of other potent interventions that could complement the treatment’s efficacy and efficiency in HIV eradication [6][7][8].
Immunometabolism is an emerging field that decrypts the mechanism of the cellular metabolic program to produce energy for robust activities when immune cells are triggered by internal or external stimuli such as pathogen infection [9]. In recent years, a substantial number of studies have attempted to uncover the complexity of the mechanism that underlies the immunometabolism process, and a new therapeutic perspective through manipulating immunometabolism has been proposed in the hope of reversing T cell exhaustion and boosting the host immune response to HIV. During chronic HIV infection, T cell exhaustion is accompanied by both elevated expression of immune checkpoint molecules and altered intrinsic metabolic programming, implying a close connection between these two events. A tilt in the balance between the two could disrupt T cell performance and provoke immune dysregulation.

2. Elevated Expression of T Cell Immune Checkpoint Molecules in HIV

The concept of T cell exhaustion was first introduced in the 1990s by Moskophidis and colleagues as they observed the disappearance and dysfunction of the CD8+ T lymphocyte in a mouse model following infection with noncytopathic strains of chronic lymphocytic choriomeningitis virus (LCMV) [10]. Following this discovery, various studies have focused on elucidating the implication of T cell exhaustion in human diseases, particularly tumor progression and chronic infections by various pathogens such as HIV, HBV, and HCV. Cellular exhaustion of CD8+ T cells is characterized by impaired capability in cell proliferation, cytokine production, and effector activity, accompanied by increased expression of immune checkpoint molecules [11][12][13][14][15][16]. At present, the term “cellular exhaustion” is no longer restricted to CD8+ T cells, as similar observations have been reported in CD4+ T lymphocytes and other immune cells [17][18].
To tackle the immune dysfunction following T cell exhaustion in viral infection, many research attempts focus on reversing exhaustion and reinvigorating T cell function by administration of an immune checkpoint blockade. Immune checkpoint molecules that are directly associated with T cell exhaustion and have shown increased expression levels during chronic HIV infection include programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). An association between these checkpoint inhibitors and HIV infection is discussed below.

2.1. PD-1

PD-1 receptor is the most extensively studied exhaustion factor that exerts a negative impact on T cells through binding to programmed death-ligand 1 (PD-L1) or PD-L2 [19]. The cytoplasmic domain of PD-1 possesses an immunotyrosine inhibitory motif (ITIM) and an immunotyrosine switch motif (ITSM) that recruit and dephosphorylate Src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2), a key signal transducer of T cell receptor (TCR) signaling [20][21]. These negative regulatory motifs are important to the cell physiology as they transduce inhibitory signals that inactivate the effector T cells, which counteracts the TCR signaling. Although this negative signal is important to prevent cell hyperactivation, an elevated expression of PD-1 in effector cells during chronic viral infections results in an undesired outcome that dampens effector activity whilst viral antigens persist in the host [11][22].
Viruses exploit PD-1 mediated suppression to evade immune surveillance and sustain their replication in the host cells. In chronic LCMV infection, increased PD-1 mediates CD8+ T cell exhaustion, whereas therapy targeting PD-1 restores T cell function and proliferation [22][23][24]. In the case of HIV infection, the HIV Tat protein induces the expression of PD-L1 via tumor necrosis factor-alpha (TNF-α) and toll-like receptor 4 (TLR4), and this negatively affects the ability of dendritic cells to recruit T cells [25]. The HIV Nef protein drives the upregulation of PD-1 during in vitro infection through its proline-rich motif and the activation of p38 signaling pathway [26]. PD-1 overexpression on CD8+ T cells is correlated with HIV viral load and disease progression [27]. During the viremia stage, HIV-specific CD8+ T cells exhibit PD-1 upregulation and exhaustion phenotypes, which could be reverted by PD-1 blockade [11][28].
Inhibition of the PD-1 and PD-L1 axis using in vitro and in vivo experiments contributes to the recovery of T cell functions [29][30][31] and potentially reverses latency in PLWH receiving HAART [32]. Nonetheless, PD-1 and PD-L1 inhibitors are currently approved only for cancer immunotherapy owing to encouraging treatment results obtained from clinical trials, but not for chronic HIV infections [33][34][35]. To date, clinical trials have suggested treatment with PD-1 inhibitors enhances the HIV-specific CD8+ response, but none has shown promise in wiping out the viral reservoir, and there is concern over immune-mediated toxicities [36][37]. A recent study demonstrates no reduction in HIV reservoir among PLWH who received anti-PD-1 drugs [38]. This suggests that the blockade of the PD-1/PD-L1 axis alone might be insufficient to tackle the HIV reservoir. Perhaps a combination therapy strategy that includes other components such as cell metabolism enhancement should be assessed to achieve viral eradication without compromising the safety of PLWH.

2.2. CTLA-4

CTLA-4 is another important negative regulator of T cell function that is upregulated during chronic viral infections and tumor growth. Upon its interaction with CD80 and CD86 ligands, CTLA-4 transduces a signal through the serine-threonine protein phosphatase 2A to inhibit nuclear factor of activated T cell (NFAT) nuclear translocation, thereby inhibiting interleukin-2 (IL-2) production and cell proliferation [39]. CTLA-4 hinders the virus-specific CD4+ and CD8+ T cell activities in chronic HIV infections despite HAART prescription [14][40], resulting in weak immune responses and a poor disease prognosis.
CTLA-4 is upregulated in HIV-specific CD4+ T cells in untreated PLWH of viremic controllers with acute and chronic infections, excluding the elite controllers [14]. The level of CTLA-4 is negatively correlated with IL-2 production but positively correlated with HIV disease progression. HIV preferentially infects CTLA+ CD4+ T cells in vitro and negatively modulates CTLA-4 expression in the presence of Nef protein to allow productive viral replication [41]. A study using HAART-treated SIV-infected rhesus macaques uncovers that memory CD4+ T cells expressing CTLA-4 contain high levels of SIV DNA and infectious virus, suggesting CTLA-4 could be an additional target for eliminating the viral reservoir [42].
FoxP3+ CD8+ regulatory T (Treg) cells expressing a high level of CTLA-4 are found to have no cytolytic potential and are directly correlated with high viremia in SIV-infected rhesus macaques [43]. A similar observation of increased CTLA-4+ FoxP3+ CD8+ Treg cells in untreated PLWH and early initiation of HAART reduces this immunosuppressive population [44]. The same study also reports the elite controllers presenting a similar level of CTLA-4 on FoxP3+ CD8+ T cells as the HIV-negative individuals, which could be associated with the maintenance of T cell antiviral responses [44].
CTLA-4 blockade in vitro leads to an increase in HIV-specific CD4+ T cell function [14]. A SIV infection in a macaque model demonstrates an increase in T cell activation and latency reversal upon CTLA-4 blockade [45]. Anti-CTLA-4 treatment in PLWH on HAART results in increased CD4+ T cell activation and a decline in plasma HIV RNA [46]. Additionally, CD8+ T cells with HLA-B*35Px restriction display CTLA-4 upregulation and acquire a functionally impaired phenotype that is reversible by in vitro anti-CTLA-4 treatment [47].
Dual blockade of PD-1 and CTLA-4 in vitro demonstrates synergistic effects and latent reversal in the proliferating CD4+ T cells [48]. A recent clinical trial has shown a positive outcome of anti-PD-1 and anti-CTLA-4 antibodies in the clearance of the HIV reservoir in PLWH with advanced malignancies, highlighting their potential applications in HIV treatment [38].

2.3. TIM-3

TIM-3 was initially identified as a T helper 1 (Th1)-specific transmembrane protein that characterizes the differentiated Th1 CD4+ T cell [49]. TIM-3 regulates T cell proliferation, production of pro-inflammatory cytokines, interferon-gamma (IFN-γ), and peripheral tolerance [50], which are driven by the binding of galectin-9, a ligand of TIM-3 [51]. The TIM-3/galectin-9 pathway triggers inhibitory signaling, reduces IFN-γ producing Th1 cells, and induces cell death in activated Th1 cells [51].
During HIV infection, viral proteins such as Nef and Vpu exert opposing effects on the TIM-3 expression level in infected CD4+ T cells. As shown by a recent in vitro study, the HIV-1 Nef protein mediates the upregulation of TIM-3 through its dileucine motif and, contradictorily, activates the infected cells through TCR signaling [52]. Conversely, Vpu protein downregulates TIM-3 surface expression on infected CD4+ T cells via its transmembrane domain and alters its subcellular localization [53]. These effects might be due to the early expression of Nef, which favors viral replication, while Vpu is expressed late to facilitate viral release.
In progressive HIV infection, high expression of TIM-3 on HIV-1-specific CD8+ T cells is correlated with the frequency of a dysfunctional T cell population [15]. Treg cells utilize the TIM-3/galectin-9 pathway to suppress proliferation of HIV-specific CD8+ T cells; the protective allele HLA-B*27- and HLA-B*5-restricted CD8+ T cells present a low level of TIM-3 upregulation that can evade the Treg cell-mediated suppression [54]. This explains why HIV elite controllers possessing these HLA alleles are able to maintain functional HIV-specific CD8+ T cells, which are responsible for delayed HIV progression [54]. Nevertheless, blocking the TIM-3 signaling pathway could restore HIV-1-specific CD8+ T cell proliferation and cytotoxic capabilities [15][55].

2.4. LAG-3

LAG-3, also known as CD223, is an immunomodulatory molecule expressed on the surface of active T cells that interacts with the TCR/CD3 complex and transduces an inhibitory signal to suppress T cell responses [56]. Significant upregulation of LAG-3 has been observed in PLWH, particularly in the activated, effector memory, and fully differentiated memory subsets of CD4+ and CD8+ T cells, which can be reduced effectively by HAART [13][18]. It is also associated with the plasma HIV viral load and disease progression [57]. Overexpression of LAG-3 in vitro in Jurkat cells causes a severe reduction in pro-inflammatory IL-2 and IFN-γ production, and ex vivo administration of LAG-3–Fc fusion protein, which disrupts the interaction of LAG-3 with its MHC II ligands, augments IFN-γ production and proliferation of HIV-specific CD8+ and CD4+ T cells [13].
LAG-3 could act synergistically with PD-1 to regulate T cell-mediated immunity [58]. Among CD8+ T cell populations, the PD-1High (Hi) LAG-3+ subset has the lowest potential in producing cytokines and performing cytolytic activity, indicating severely impaired T cell function [59]. During chronic HBV and LCMV infection, the functionality of exhausted CD4+ and CD8+ T cells with high PD-1 and LAG-3 could be partially restored after blocking both inhibitory receptors [60][61][62]. Limited evidence of LAG-3 blockade has been shown in the case of HIV infection.

2.5. TIGIT

TIGIT is a co-inhibitory molecule that is expressed on different T cell subpopulations, including active, memory, exhausted, follicular helper, natural killer (NK), and Treg cells [63][64][65]. TIGIT attenuates the TCR signal and induces the release of anti-inflammatory IL-10 while inhibiting the production of pro-inflammatory IL-12; TIGIT-knockout mice generate high levels of pro-inflammatory cytokines and a reduced level of IL-10 compared to their wild-type counterparts [66][67].
Indeed, increased expression of TIGIT has been detected on HIV-specific CD8+ T cells with poor functionality in PLWH, suggesting this subset represents an exhausted phenotype [68]. In accordance with the finding, a recent study demonstrates that the TIGIT+ NK cells derived from PLWH lose the capability to produce TNF-α, IFN-γ, and CD107a, which are positively associated with viral load [69]. Co-expression of PD-1, TIGIT, and LAG-3 can be determined as markers of dysfunctional HIV-specific T cells during viral persistence [16][18]. In CD8+ T cells derived from cancer patients, TIGIT is upregulated along with PD-1, and combination therapy invariably results in a significant outcome of tumor growth inhibition [70][71]. A recent study demonstrates that the combination blockade of LAG-3, CTLA-4, or TIGIT increases the frequency of cells expressing CD107a and IL-2, which are associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in HAART-treated PLWH [72].

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