Although acquired immune deficiency syndrome (AIDS) has been known for decades, it remains a thorny problem in humankind. Fortunately, since the emergence of antiretroviral therapy (ART), AIDS has turned into a kind of chronic disease, from a fatal threat. Although ART can restrain human immunodeficiency virus type 1 (HIV-1) replication, the long-term toxicity of some antiretroviral drugs has been a severe problem that may damage treatment effectiveness. In addition, the adherence and availability of ART decreased during the coronavirus disease 2019 pandemic, exposing the vulnerability of this lifelong treatment. Thus, a safer and more effective cure for AIDS is an urgent need for the increasing number of people living with HIV-1 (PLWH).
Over the last decade, various studies have revealed the link between immunity and metabolism. Metabolic reprogramming is necessary for the function of the immune system, because of the functional requirements of different immune cells. One of the most critical energy sources is glucose, which can be exploited by cells via oxidative phosphorylation (OXPHOS) and glycolysis to produce adenosine triphosphate (ATP). The proper functioning of immune cells is inseparable from the normal operation of three metabolic pathways, which are glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway (PPP).
On one side, a growing number of researchers find that HIV-1 can urge the infected CD4+ T cells to plunder the source and energy, which is significantly important for viral replication. On the other side, further studies suggested that glucose metabolic pathways also control host responses to HIV-1 infection. Thus, the interplay between glucose metabolism and HIV-1 is worth exploring and may result in novel therapeutic targets and promising therapeutic strategies against AIDS.
Alteration of glucose metabolism in HIV-1 target cells
HIV-1 can infect both CD4+ T cells and macrophages. However, they have significantly different glucose metabolic spectrums during the viral life cycle [Figure 1].
CD4+ T cells
There is a point that HIV-1 hijacks the host resources to meet the need for its replication and transcription. In addition, its replication will be eliminated in the CD4+ T cells cultured in the presence of 2-deoxy glucose, a competitive inhibitor of glycolysis, or the absence of glucose. The whole process of how HIV-1 alters the glucose metabolism of host CD4+ T cells can be divided into three categories: glycolysis, the PPP, and the TCA cycle.
Glycolysis is a series of reactions that extract energy from glucose by splitting it into two three-carbon molecules called pyruvates. It has been previously reported that, in primary CD4+ T cells, the flux through the glycolytic pathway is increased in the case of HIV-1 infection. A further report from Kavanagh Williamson showed that co-overexpression of glucose transporter (GLUT) 1, GLUT3, GLUT4, and GLUT6 in primary CD4+ T cells infected with HIV-1 could increase glucose uptake and expand levels of glycolytic intermediates. One of the key Glut1 regulating pathways is the PI3K-Akt pathway. The mTOR signaling molecule is one of the crucial downstream targets in this pathway, which is a critical kinase that modulates cell growth and controls cell metabolism in response to environmental signals. mTOR protein consists of two complexes with distinct functions: mTORC1 and mTORC2. However, there is no direct evidence to identify the link between GLUT1 and PI3K/Akt/mTOR signaling pathway, so how HIV-1 regulates the expression of GLUT1 is still unclear. CC-chemokine ligand 5, the ligand of CC-chemokine receptor 5 (CCR5) can increase cell surface expression of the glucose transporter GLUT1 and help the glucose uptake in an mTOR-dependent manner, which plays an important role in breast cancer cell lines. It provides a hypothesis that this effect could be reproduced in HIV-1 infection of CD4+ T cells because of the potential role of HIV-1 gp120, which has been reported that can compete with CC-chemokine ligand 5 for binding to CCR5. Similarly, other studies showed that HIV-1 gp120 could enhance glycolysis in glioma cells. Besides this function, extracellular levels of ATP can be resulted from gp120, which can bind to purinergic receptors and facilitate virus to entry host cells after binding to CCR5 or CXC-chemokine receptor 4 (CXCR4). On the other side, not only the expression of GLUT1 is upregulated but also glycolytic enzyme activity has a highly significant increase in HIV-1–infected CD4+ T cells. For example, the elevated of hexokinase1 HK1 activity was obscured, and the functionally related voltage-dependent anion channel protein can respond to the infection of CD4+ T cells with HIV-1.
Hypoxia-inducible factor 1α (HIF-1α), the most studied molecule in the field of immune metabolism, plays a central role in modulating glycolysis in HIV-1 infection. HIF-1α induced by the mTORC1 directly promotes the transcription of glycolytic enzymes. Other studies proved that HIF-1α knockdown decreased the messenger RNA levels of glycolysis genes such as Glut1, PFKP, and PDK1 in T cell lines to wild-type levels. During the HIV-1 replication cycle, the infected CD4+ T cells generate cytosolic double-stranded DNA, increasing the mitochondrial reactive oxygen species (ROS)–dependent stabilization of the HIF-1α. In addition, HIV-1 also induces the cell surface expression of CXCR4 through the HIF-1α pathway to facilitate the infection. Some HIV-1 proteins might also upregulate glycolysis. For example, HIV-1 Vpr protein alters the host cell metabolism, resulting in mitochondrial dysfunction and dysregulation of glycolysis. Compared with the blank control group, metabolites and metabolic enzymes had a significant change in CD4+ T cells treated with Tat, which is an important protein in HIV-1 provirus transcription. Moreover, it was reported that the function of HIV-1 Tat protein might be associated with the mTOR pathway.
PPP has two distinct phases in the pathway. The first is the oxidative phase, in which nicotinamide adenine dinucleotide phosphate (NADPH) is generated, and the second is the nonoxidative synthesis of five-carbon sugars. These metabolites participate in the synthesis of deoxyribonucleoside triphosphates (dNTPs) and oxidate stress reaction, which are necessary for HIV-1 reverse transcription and latency. One of the most important regulators of HIV-1 replication is the level of dNTPs pools in host cells, which determines the effect of HIV-1 reverse transcriptase (RT). Some studies have confirmed that the activation of mTOR pathways increases the level of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP, which indicates a potential association between the mTOR signaling pathway and dNTPs pools. The activation of mTOR following T cell stimulatory signals enables the expansion of dNTPs pools to fuel HIV-1 RT and promotes acetyl-CoA to stabilize microtubules, which can help transporting RT products. By contrast, rapamycin-induced mTOR inhibition can diminish the size of the pools; thereby, HIV-1 infection is repressed.
NADPH, the primary source of cellular reductant, plays an important role in both biosynthesis and protection from oxidative stress. A recent study suggests that oxidative stress can be induced by HIV-1 infection, followed by the activation of Nrf2, the master transcriptional regulator, which controls the production of NADPH. Moreover, ROS content and antioxidant responses partially downregulate during HIV-1 latency.
TCA cycle and OXPHOS
TCA cycle, also known as Krebs cycle or the citric acid cycle is a series of chemical reactions that occur in the mitochondria. Therefore, pyruvate is oxidized to the TCA cycle intermediates to produce a lot of ATP via OXPHOS. Glutamine is a precursor for a-ketoglutarate (α-KG) of the TCA cycle, which is related to the activation of mTORC1. Some cases show that ASCT2, a primary glutamine transporter, is highly expressed in HIV-1–infected CD4+ T cells, which leads to increased glutamine uptake and α-KG production. In addition, exogenous α-KG is the key to promoting HIV-1 reverse transcription, making CD4+ T cells more sensitive to infection.
Recently, researchers have focused more on OXPHOS reaction. They found that it might be the key factor of HIV-1 infection in CD4+ T cells, not glycolysis. Some recent works support this point. It is suggested that an enhancement of OXPHOS is associated with HIV-1 infection. Moreover, high expression of the nucleotide-binding domain and leucine-rich repeat-containing receptor X1 (NLRX1) can be induced by HIV-1 infection, which interplays with the mitochondrial protein FASTKD5, thereby leading to the elevated OXPHOS pathway and increasing HIV-1 replication in CD4+ T cells.
Glucose metabolism regulates CD4+ T cells differentiation and function
There is a complex relationship between glucose metabolism and the differentiation of CD4+ T cells. As well as what was mentioned previously, increased glycolytic pathway results in the activation of mTOR and HIF-1α. Some studies suggest that CD4+ T cells can differentiate into Teff or Treg subsets, which have different kinds of metabolism. Furthermore, it is glycolysis that plays an important role in Th1 and Th2 differentiation.[32,33] Further studies showed that mTOR plays a central role in the fate of CD4+ T cells. mTOR activation leads to CD4+ T cells differentiation to Teff subsets. On the contrary, mTOR suppression by rapamycin could result in Treg induction. Meanwhile, the differentiation of Tfh cells also relies on the mTORC1 and mTORC2 control.
Moreover, other reports demonstrate that HIF-1α induced by the mTOR signal was selectively expressed in Th17 cells. After the knockdown, Th17 cell development was diminished, but Treg cell differentiation was enhanced. In addition, HIF-1α negatively regulates Th1 function.
Bystander CD4+ T cells
Although HIV-1 infection significantly alters the metabolic pathways in infected CD4+ T cells, the number of HIV-1–infected cells in patients is relatively low, and the majority of CD4+ T cells are uninfected bystander cells. Sadly, there are few studies paying attention to the glucose metabolism in these bystander cells. All we only know is that apoptosis of uninfected bystander cells plays a significant role in disease progression. In the past few years, it has been demonstrated that apoptosis of uninfected bystander cells mediated by HIV-1 envelope glycoproteins (Env), composed of gp120 and gp41, plays an important role. Although further study reported that Env-induced oxidative stress is responsible for their death by apoptosis, its underlying mechanism is still unclear. According to the context, we propose a hypothesis that Env expressed at the surface of infected cells might induce apoptosis in uninfected bystander CD4+ T cells via altering glucose metabolism such as promoting glycolysis and OXPHOS to lead to an accumulation of ROS.
Compared with higher glucose uptake and larger metabolite pool sizes in HIV-1–infected CD4+ T cells, macrophages show substantial reductions in glucose uptake and glycolytic intermediates. Some studies suggest that HIV-1 hijacks the glucose metabolism in acutely infected macrophages through the HIV-1 Vpr-HIF-1α axis, which contributes to increasing the expression of enzymes in PPP and pyruvate metabolism and decreasing the expression of some critical mitochondrial enzymes. Although most macrophages infected with HIV-1 died, there is still a small population surviving with latent HIV-1 reservoirs. Compared with the acute infection phase, macrophages with latent HIV-1 reservoirs have significantly distinct glucose metabolism, characterized by mitochondrial fusion and reduced mitochondrial ATP production. However, no changes in glycolysis were observed.
Alteration of glucose metabolism in immune subsets that limit HIV-1 infection in PLWH
PLWH is the abbreviation for people living with HIV. During persistent HIV-1 infection in PLWH, hyperimmune T cells are gradually exhausted, characterized by low proliferation and high expression of the inhibitory receptor programmed death-1 (PD-1). Meanwhile, long-term antigen exposure irreversibly causes many defects in glucose metabolism enzymes, thereby exhibiting decreased glycolytic flux and restricted respiratory ability. An intimate relationship between high expression of PD-1 and low glycolytic flux has been revealed.[45,46] Some studies showed that, in preactivated T cells with PD-1, ligation could inhibit subsequent Glut1 upregulation and expression of HK2 resulting in turning off their glycolysis metabolism. However, blockade of inhibitory receptor PD-1 failed to shift their metabolism toward glycolysis in effector T cells. It implies that glycolysis only has indirect contact with the PD-1 signal pathway. A successive study pointed out that mitochondria might be the main targets of PD-1 inhibitory activity, not glycolysis.
Most of the individuals living with HIV-1 are using ART to control viremia and delay disease progression, which enables similar life expectancy to healthy people. Despite preventing more CD4+ T cells from getting infected, long-term ART still has limitations. For example, ART can induce a multitude of injuries to mitochondrial function such as elvitegravir, and dolutegravir exhibits significantly decreased cellular respiration in a dose-dependent manner. In addition, this adverse effect might be associated with ROS production. Because of the adverse effect of gaining weight in ART-treated individuals, metabolic syndrome is common in PLWH, and it may be indirectly caused by ART-associated fat gain and insulin resistance.
CD8+ T cell is a key factor in eliminating virus-infected cells. During the acute infection period, monocytes upregulate the expression of GLUT1 and activate the mTOR signal pathway to increase the glycolysis flux, which significantly elevates the function of effect CD8+ T cells to kill the targets. However, during chronic HIV-1 infection, baseline glycolysis levels were similar to those of uninfected people in the exhausted CD8+ T cells. Interestingly, the level of glycolysis in CD8+ T cells from elite controllers (ECs) is similar to uninfected people. Instead, the messenger RNA levels of several negative regulators of glycolysis upregulate in ECs. Further studies show that specific CD8+ T cells from antiretroviral treated noncontrollers largely depend on glucose, whereas those from ECs have more diverse metabolic resources. Transient controllers are a kind of ECs that lost spontaneous control. However, before the loss, transient controllers show a specific metabolomic profile characterized by glycolysis changes and deregulated mitochondrial function.
Further studies suggest that mTOR signaling may play a remarkably critical role in regulating CD8+ T cell function from ECs. In addition, the recent report also indicates that elevated HIF signaling was detected as a signature of the male ECs phenotype. After stimulation of TCR and activation of the PI3K/Akt pathway, glycolysis was also increased in memory CD8+ T cells, which is required for rapid interferon γ production. These evidences point out that PI3K/mTOR/HIF-1α pathway may play a critical role in CD8+ T cells from ECs.
Cellular metabolism influences the course of HIV-1 pathogenesis
HIV-1, which is an obligate intracellular parasitic organism, lacks the metabolic machinery that is necessary for its survival and depends on various materials from host cells. HIV-1 infection alters the glucose metabolism of host cells for its replication and viral production. Therefore, the variety of glucose metabolism in host cells conversely impacts the course of HIV-1 pathogenesis, and the levels of metabolism in the subsets of CD4+ T cells differ from each other.
HIV-1–susceptible cells have a distinct glucose metabolic profile. In some cases, CD4+ T cells upregulate the expression of CXCR4 and HIF-1α, enhancing the entry of HIV-1 in a high glucose environment. Similarly, activated CD4+ T cells based on high glycolysis and OXPHOS activity are significantly susceptible to HIV-1 infection.[7,29] Moreover, partial inhibition of glycolysis not only impaired HIV-1 infection but also prevented HIV-1 amplification in host cells.
The specific glycolysis profile in host cells is the hallmark of HIV-1 latency. In primary CD4+ T cells, the replication of HIV-1 results in an enhancement in glycolytic flux, which is particularly important for viral production. On the contrary, recent studies demonstrate that transition to latent HIV-1 infection downregulates glycolysis, instead of relying on the parallel PPP; howbeit, viral reactivation restores it. The main product of PPP is NADPH, which reduces the flux of glycolysis via downregulating glucose 6 phosphates, as well as inducing HIV-1 latency.
The basal glycolytic state is a determinant of HIV-1 fusion and adequate packaging. During the acute HIV-1 infection, high glycolysis flux offers sufficient cholesterol in CD4+ T cells. Further studies show that adequate cell surface cholesterol is necessary for HIV-1 fusion by affecting membrane order and tension. In some cases, glycolysis also contributes to recruiting viral components into HIV-1 particles and maintains the enzymatic activity of RT.
Potential application of metabolic features of HIV-1 infection
Some cases suggest that the proportion of CD4+ Glut1+ T cells can be exploited as a prognostic marker for CD4+ T-cell loss during AIDS progression because of the positive correlation with the cellular activation marker, HLA-DR. Similarly, other cases show that a high percentage of CD4+ Glut1+ T cells was associated with poor levels of T-cell recovery in HIV-1–positive patients with ART. That means that the levels of GLUT1 may be a promising biomarker for evaluating AIDS progression. Another clinical trial revealed that 18F-fluorodeoxyglucose positron emission tomography–computed tomography could help identify high-risk patients with potential immune reconstitution inflammatory syndrome after ART treatment. In addition, this technique is based on the theory that immune reconstitution inflammatory syndrome is associated with increased glycolysis.
The metabolic reprogramming of T cells transforming glycolysis into OXPHOS may revive the activity and capability of these cells to restrict viral infection, and some cytokines have the potential function to shift the glucose metabolism in T cells. As previously discussed, interferon α, for instance, induces the activation of inflammation and increases glycolysis in T cells, and interleukin 7 upregulates the expression of cell surface GLUT1, thereby increasing glucose uptake and glycolysis flux. These are key factors why some T cells are susceptible to HIV-1. Interleukin 15 has also been reported that it can help the survival and proper function of HIV-1–specific CD8+ T cells via improving the production of mitochondria.
Regarding target cells of HIV-1 infection, restrain the glucose metabolism that can efficiently block HIV-1 replication. For example, treatment with dexamethasone, which is a known as glycolysis inhibitor, decreases the baseline percentage of infected cells expressing HIV-1 transcripts. It has been shown that rapamycin, an inhibitor of the mTOR signal pathway, reduces HIV-1 replication and transcription. In the strategy of combination with immune activation, it relieves the effects of various toxic cytokines produced by the inflammatory response. Metformin, a widely used antidiabetic drug, was recently shown to modulate T-cell activation and inflammation by suppressing the mTOR pathway. A small-scale clinical trial suggests that metformin decreased mTOR activation and the HIV-1 RNA/DNA ratios in colon-infiltrating CD4+ T cells of 8/13 nondiabetic ART-treated PLWH.
Tumor cells rapidly consuming glucose through metabolic reprogramming compete with immune cells for the main energy resources. Owning to the lack of glucose, the function and differentiation of immune cells are seriously restricted. Likewise, HIV-1 selectively infects the active metabolic profile of CD4+ T cells and hijacks the glucose metabolism of the host cells, thereby increasing glycolysis and producing many metabolites for viral replication. Nowadays, adjusting tumor metabolism has become a novel strategy for cancer therapy in treating various intractable malignancies. It is reasonable to assume that further studies on cancer metabolic therapy might provide new therapeutic avenues for HIV-1 treatment. As mentioned previously, glucose metabolism is so important for HIV-1 infection that, if we disturb the metabolic reprogramming in infected CD4+ T cells, the course of viral pathogenesis will be in suspended animation. In addition, the mTOR pathway regulated by both immunity and metabolism signals plays a key role in this process. It is not only associated with the expression of GLUT1 but also the differentiation of T cells, which provides a starting point for us to explore the HIV-1 related immune metabolism.
Existing evidences support that active glucose metabolism positively affects the susceptibility of HIV-1 infection, as well as altered glucose metabolism, in HIV-1–infected primary CD4+ T cells, whereas the role of glucose metabolism in viral latency and in promising therapeutic strategies has remained indistinct. One recent case implied that the downregulation of glycolysis in long-term infected cells is characterized for the latency of HIV-1. On the contrary, the latest study showed that, compared with uninfected T cells (Jurkat), three latently HIV-1–infected T cells (CA5, EF7, and CG3) produced significantly more lactate, confirming the metabolic preference for glycolysis. Therefore, the specific relationship between HIV-1 latency and glucose metabolism is worthy of exploration in the future.
Kai Deng conceived the article. Zhonghe Chen and Tiantian Wang collected the literature and drafted the original manuscript. Kai Deng critically revised the manuscript. All authors approved the final manuscript.
Conflicts of Interest
Editor note: Kai Deng is the editor of Infectious Diseases & Immunity. The article was subject to the journal's standard procedures, with peer review handled independently by this editor and his research group.
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