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'Block & Lock' Cure Approach - Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging
 
 
  https://f1000research.com/articles/7-125/v1
 
"Despite effective anti-retroviral therapy (ART), two key clinical challenges remain elusive. First, HIV remains in latent reservoirs within CD4+T cells and possibly macrophages….. The second critical challenge in the ART era is the increased prevalence of age-related comorbidities such as cardiovascular disease, non-AIDS cancers, bone and renal disease, and frailty in virologically suppressed ART-treated persons. This commentary will discuss a new and arguably controversial HIV cure strategy—"block and lock"—used to suppress reservoir activation33, an emerging paradigm supported by new insights of metabolic regulation of latency. In addition, we will discuss targeting of host immune cellular machinery as an approach to circumvent the threat of HIV resistance against current treatments as well as to control chronic HIV-associated chronic inflammation and the related development of non-communicable comorbidities."
 
Abstract
 
An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of "inflammaging", a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV+ individuals.
 
Metabolic inhibition to "block and lock" the HIV reservoir
 
The setbacks from clinical trials employing the "kick and kill" approach to eradicate HIV74,75 have forced researchers to re-think and explore alternative cure strategies, including the provocative "block and lock"76 and "starve"36,77,78 approaches. These methods attempt to control viral persistence by metabolic suppression of cells harboring HIV proviral DNA to subdue reactivation and homeostatic proliferation of reservoir cells. Recent data by Heredia et al. have brought support to this shifting chain of thought by demonstrating that HIV hyperactivates mTORC1 activity in a PI3Kinase-dependent manner promoting the synthesis of biomolecules for virion production and latent viral reactivation71. Furthermore, inhibition of mTORC1 or PI3Kinase can successfully inhibit viral replication and viral reactivation as a result of a decrease in cellular biosynthesis3,79. A confirmatory role of the involvement of mTOR in controlling HIV latency was also established by employing a genome-wide screen approach by Verdin et al., who used different HIV latency models and HIV-infected patient primary cells76. They have shown that the dual mTOR inhibitors Torin1 and pp242, which both target the two mTOR complexes (mRORC1 and mTORC2), strongly suppressed latent HIV reactivation following potent CD4 T-cell activation through the T-cell receptor76. Furthermore, inhibition of these complexes abrogated both Tat-dependent and Tat-independent transactivation of the HIV promotor76. Thus, whereas the "block and lock" predominantly focusses on limiting the transcription of latent HIV DNA through mTOR suppression, the "starve" model earlier proposed by Palmer et al. posits subduing the metabolic activity of reservoir cells to limit homeostatic proliferation while controlling the metabolic state within T cells and macrophages, essential for viral infectivity36,78.
 
mTOR and latency-reversing agents: toward an HIV cure
 
Recent work by Siliciano's group has provided an experimental model supporting an interesting combination approach by which mTOR drugs could mitigate LRA-mediated inflammatory responses and toxicity while maximally reactivating the HIV reservoir80. In their in vitro latency model, rapamycin did not inhibit HIV reactivation in a dose-dependent manner in activated CD4+ T cells from individuals on suppressive ART. These results are compatible with the finding that rapamycin inhibits mTORC1 but not mTORC2. The action of rapamycin on mTORC1 causes repression of the basal transcription of HIV long-terminal repeat (LTR) without affecting Tat-mediated transactivation of the virus81. Inhibition of mTORC2, on the other hand, appears to inhibit both basal transcription and tat-mediated HIV transcription71. However, rapamycin drastically reduced the secretion of pro-inflammatory cytokines and suppressed the proliferation of CD4+ T cells from these patients. Furthermore, rapamycin reduced the expression of the T-cell exhaustion marker PD-1 while preserving basal CTL-mediated killing of infected cells80. However, other pro-inflammatory factors produced by activated CD4+ T cells (for example, inflammatory lipids such as ceramides) may result in clinically deleterious inflammatory responses that may not be diminished by mTOR inhibitors. Nonetheless, the observational study by Stock et al., in which rapamycin treatment of HIV+ kidney transplant recipients caused reduced frequency of T cells harboring HIV DNA, will likely encourage clinical trials aimed at specifically examining the effects of mTOR inhibitors and their impact on the HIV reservoir size82.
 
Importantly, the impact of these and other glucose metabolic inhibitors (for example, those targeting specific PI3Kinase isoforms, Glut1, and hexokinase II) on potential long-term remission in ART-treated virologically suppressed HIV+ individuals should be carefully evaluated. In addition, it is likely that a multidisciplinary approach that includes a combination of therapies will be necessary to achieve HIV eradication or ART-free sustained HIV control. Recently, the success of immunotherapy targeting the inhibitory receptors PD-1, CTLA-4, and other immune-negative checkpoints in recovering T-cell immunity has promoted interest in using similar strategies to achieve HIV eradication.
 
T-cell exhaustion is a process that depends on metabolic changes driven by signaling through these negative immune checkpoints83; it has been shown that blocking immune checkpoints has differential effects on cell metabolism, depending on which molecule is targeted by the blockade84,85. Therefore, evaluation of the impact of immune checkpoint blockade therapy on cellular immunometabolism machinery may have relevance in the setting of HIV. Furthermore, combining immunotherapy and metabolism-based therapies can be another potential targeted strategy and warrants further investigation.
 
Metabolic rewiring of monocytes/macrophages primes host inflammatory and defense mechanisms
 
Like activated T cells, Glut1 is the main inflammatory-responsive glucose transporter on activated monocytes and allows high glucose uptake required to fuel glycolysis. We have shown that, in ART-treated HIV-infected patients, Glut1 is profoundly increased on pro-inflammatory monocytes9. Also, Freemerman et al. have found that inflammatory M1 macrophages have overwhelmingly high glycolytic activity and Glut1 expression via in vitro experiments using murine macrophages64.
 
However, cytokine production by M2 polarized human macrophages has also been shown to rely on glycolytic metabolism in addition to fatty acid oxidation (FAO). Control of this glycolytic state provides the metabolic basis by which interleukin-10 (IL-10) exerts its anti-inflammatory effects. For example, IL-10 opposes lipopolysaccharide (LPS)-induced glucose uptake and glycolysis in macrophages and promotes OXPHOS in an mTOR-dependent manner30. However, it should be noted that, unlike LPS alone, complex microbial stimuli can induce specific metabolic reprogramming that involves upregulation of OXPHOS, glycolysis, and FAO to prime host defense mechanisms, including cytokine production and phagocytosis.
 
Immunometabolism offers new opportunities to control inflammation and age-related comorbidities in ART-treated HIV+ individuals
 
In our earlier work, we indicated that cell-surface Glut1 levels on pro-inflammatory monocytes (the intermediate CD16+ monocyte subset) correlated significantly with inflammatory plasma biomarkers of inflammation and cardiovascular disease risk9. Furthermore, Glut1-expressing monocytes exhibit higher levels of intracellular tumor necrosis factor (TNF) compared with Glut1-negative cells9. However, although several models have been proposed to connect monocyte glucose metabolic dysfunction with age-related comorbidities36,86, experimental evidence has only recently come together to support these models.
 
Analysis of monocytes from HIV-infected participants enrolled in the Women's Interagency HIV Study showed that the frequency of circulating Glut1-expressing intermediate monocytes is significantly elevated in those with subclinical cardiovascular disease10. Furthermore, in a group of aging HIV+ men on suppressive combined ART, frailty (evaluated using the Frailty Index) was associated with Glut1 expression on total monocytes87. Since monocyte metabolic activation may contribute to the development of age-related comorbidities such as atherosclerosis in ART-treated HIV+ persons, Glut1 is potentially a novel target to limit inflammation. One may argue against the use of metabolic inhibitors as potential immunomodulators in the context of inflammatory diseases such as HIV infection in fear of deleterious side effects. However, it is worth noting that glucose uptake by insulin-sensitive cells such as adipocytes and myocytes is controlled by other glucose transporter isoforms (for example, Glut4), which are less responsive to inflammatory signals compared with Glut188. Furthermore, specific PI3Kinase isoforms such as PI3Kγ and PI3Kδ which control mTOR and glucose metabolism are restricted to immune cells, thereby circumventing or limiting potential side effects. The unwavering interest in immunometabolism by biotechnology companies and the current intersection between immune cell metabolism and the cancer field now provide great opportunities for re-purposing some cancer drugs to treat pathogen-driven inflammatory and non-communicable diseases36,89.
 
Key points and conclusion
 
Lack of knowledge regarding the precise mechanisms underlying viral persistence and chronic inflammation in HIV infection has hampered the development of host-directed therapies to eradicate the HIV reservoir and control chronic inflammation in HIV-infected persons. Recent work has exposed previously unrecognized alterations in cellular energy metabolism in immune cells in HIV+ individuals. In addition, the critical role of glucose metabolism, regulated by Glut1 and mTOR, in controlling HIV replication, latency, and inflammatory responses has been established (Figure 1).
 
Figure 1. CD4+ T cells reprogram glucose metabolism during infection from oxidative phosphorylation (OXphos) toward glycolysis marked by increased cell surface Glut1 and mTOR activation.
 
(a) mTOR regulates HIV transcription critical for viral reactivation and ongoing replication. Glycolysis regulated by mTOR provides precursors for DNA and cell wall synthesis which support homeostatic proliferation of infected CD4+ T cells. (b) Similar to CD4+ T cells, mTOR/PI3Kinase regulates monocyte/macrophage Glut1 cell surface expression and metabolism. A metabolic shift toward glycolysis supports pro-inflammatory cytokine production in monocytes/macrophages. Glut1, glucose transporter 1; mTOR, mechanistic target of rapamycin.
 
More studies evaluating different classes of glucose metabolic inhibitors directed against immune cells are warranted to justify their use in HIV-infected individuals. Furthermore, modulating glucose metabolic activities could be either beneficial or detrimental depending on the infection stage in which they are administered34,90. It will also be important to delineate the additional pathways that control glucose metabolism, including mitochondrial biogenesis, as additional therapeutic target options. The main challenge in identifying new metabolic networks will be the adoption of new technologies to interrogate metabolism in small blood samples typically available from clinical testing. New technologies such as the Seahorse extracellular flux analyzer have helped to revolutionize the field; however, the readout gives only a global snapshot of oxidative and glycolytic metabolism. In order to fully address the complex questions of how metabolic remodeling of immune cells contributes to the course of HIV infection, additional technologies, such as those employing multiparametric techniques to study specific subpopulations of immune cells (reviewed in 28), are needed.

 
 
 
 
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