Antiretroviral therapies efficiently block HIV-1 replication but need to be maintained for life. Moreover, chronic inflammation is a hallmark of HIV-1 infection that persists despite treatment. There is, therefore, an urgent need to better understand the mechanisms driving HIV-1 pathogenesis and to identify new targets for therapeutic intervention. In the past few years, the decisive role of cellular metabolism in the fate and activity of immune cells has been uncovered, as well as its impact on the outcome of infectious diseases. Emerging evidence suggests that immunometabolism has a key role in HIV-1 pathogenesis. The metabolic pathways of CD4+ T cells and macrophages determine their susceptibility to infection, the persistence of infected cells and the establishment of latency. Immunometabolism also shapes immune responses against HIV-1, and cell metabolic products are key drivers of inflammation during infection. In this Review, we summarize current knowledge of the links between HIV-1 infection and immunometabolism, and we discuss the potential opportunities and challenges for therapeutic interventions.
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The authors thank the members of the Sáez-Cirión and Sereti laboratories for discussions. A.S.-C. acknowledges funding from Institut Pasteur (GPF LINMEC programme, project METINFECT), MSDAVENIR, ANRS, Sidaction and amfAR (108687-54-RGRL and 108928-56-RGRL) related to his work on this subject. The work of I.S. was supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases (NIAID)/NIH.
A.S.-C. is listed as inventor in a patent application submitted by Institut Pasteur based on the potential of metabolic modulators to counteract HIV-1 infection.
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Nature Reviews Immunology thanks P.-C. Ho, D. Russell and L. Trautmann for their contribution to the peer review of this work.
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A metabolic process in which glucose is broken down to obtain energy and carbon products.
- Tricarboxylic acid cycle
(TCA cycle; also known as the citric acid cycle or Krebs cycle). A series of chemical reactions that occur in the mitochondria and that transform carbon products into ATP.
- Pentose phosphate pathway
(PPP). A pathway of glucose metabolism that parallels glycolysis and generates ribose for the synthesis of nucleotides, amino acids and NADPH.
- Fatty acid oxidation
(FAO). The degradation of fatty acids in mitochondria to obtain ATP.
- Fatty acid synthesis
(FAS). A metabolic process that uses citrate from the tricarboxylic acid cycle to produce fatty acids and lipid-based structures.
- Amino acid metabolism
A metabolic process in which amino acids such as glutamine are broken down to feed the tricarboxylic acid cycle and obtain energy.
- Oxidative phosphorylation
(OXPHOS). A process that generates ATP as a result of the transfer of electrons from energy-rich molecules produced in the tricarboxylic acid cycle to oxygen.
- Macrophage polarization
The process by which macrophages produce distinct functional phenotypes as a reaction to specific microenvironmental stimuli and signals. ‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with interferon-γ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.
- P-TEFb complex
(Positive transcription elongation factor b complex). A heterodimer of cyclin-dependent kinase 9 and one cyclin T1, cyclin T2 or cyclin K subunit. P-TEFb recruitment to the HIV-1 promoter by the HIV-1 factor Tat is crucial for efficient HIV-1 transcriptional elongation and expression.
A post-translational modification of histones consisting of the modification of lysine residues by the introduction of crotonyl groups from crotonyl-CoA derived from fatty acid synthesis.
- T cell exhaustion
A T cell state that involves loss of effector functions and memory potential as a consequence of persistent stimulation by antigens or activation signals. It is associated with the upregulation of expression of inhibitory receptors such as PD1.
- Precursor exhausted T cells
A recently identified subset of T cells that share some characteristics with both classical exhausted T cells and classical memory T cells. They are thought to replenish the pool of exhausted T cells.
- Late presenters
Individuals who present for clinical care at an advanced stage of HIV-1 infection, with either very low CD4+ T cell counts or AIDS-defining events.
- Immune reconstitution inflammatory syndrome
An aberrant and highly inflammatory response to an existing HIV-1 infection that sometimes occurs during the recovery of the immune system after initiation of antiretroviral therapy.
- Shock and kill strategy
A strategy aiming at HIV-1 cure that consists of reactivating latent proviruses from the persistent viral reservoir (shock) so that all infected cells can then be eliminated (kill).
- Block and lock strategy
A strategy aiming at HIV-1 remission that consists of reinforcing the mechanisms repressing HIV-1 transcription (block) and increasing the threshold required for reactivation signals (lock), so that latency can be maintained for long periods of time after interruption of antiretroviral therapy.
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Sáez-Cirión, A., Sereti, I. Immunometabolism and HIV-1 pathogenesis: food for thought. Nat Rev Immunol 21, 5–19 (2021). https://doi.org/10.1038/s41577-020-0381-7
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