Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects

Dagenais-Lussier, Xavier; Aounallah, Mouna; Routy, Jean‐Pierre; Tremblay, Cécile; Sékaly, Rafick‐Pierre; El-Far, Mohamed; Grevenynghe, Julien van

doi:10.1016/j.cytogfr.2015.09.001

Cited by 44 publications

(34 citation statements)

References 148 publications

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“…Tryptophan catabolism into Kyn is driven by the IDO-1 enzyme expressed by monocyte/macrophages and DCs. Several soluble factors associated with immune activation, including IFN-␥, tumor necrosis factor alpha, IL-1␤, sCD40, IL-32, and Toll-like receptor ligands, are known to induce IDO-1 activity in these cells (42). Strain-dependent HIV-1 infection and Tat expression also lead to increased IDO-1 activity in innate immune cells (47).…”

Section: Ccr7mentioning

confidence: 99%

“…As early HIV-1 infection is characterized by persistent inflammation and enhanced tryptophan catabolism (22,(24)(25)(26)(27)42), we first evaluated the levels of several proinflammatory molecules and Kyn in plasma from the PHI, CHI, and HIV free subjects. Consistent with earlier reports (22,25,43), we found higher levels of IL-6, sCD14, IP-10, and Kyn in PHI and CHI subjects than HIV free donors (Fig.…”

Section: Loss Of Memory Cd4 T Cells During Hiv-1 Infection Involves Dmentioning

confidence: 99%

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Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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Section: Ccr7mentioning

confidence: 99%

Section: Loss Of Memory Cd4 T Cells During Hiv-1 Infection Involves Dmentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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“…A novel approach involving control of immune activation combined with optimal "immunometabolic conditioning fitness" for immune cells represents an attractive direction. [12] Collectively, the strategy to enhance the contribution of broadly neutralizing antibody along with CD8 T-cell response in the context of controlled immune activation and optimal metabolic fitness will mark the dawn for HIV vaccine success.…”

Section: Hiv Vaccine Research: Beyond the Hubris Nemesis Complexmentioning

confidence: 99%

HIV immunotherapy comes of age: implications for prevention, treatment and cure

Routy

Mehraj

Cao

2015

Expert Review of Clinical Immunology

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Antiretroviral therapy (ART) has reshaped the lives of millions of individuals infected with human immunodeficiency virus (HIV). Patients initiating ART early in the course of infection benefit from a considerable reduction in the risks of acquired immune deficiency syndrome (AIDS) and HIV-related inflammatory events. However, the absence of cure and lifelong requirements of treatment highlight the need of a vaccine and an immunotherapeutic strategy. Like for cancer, a paradigm shift has occurred with the contribution of immune activation and microbial translocation priming aberrant systemic immunity in restricting the ability of the host to mount an effective immune response. The approaches of implementing an effective vaccine to prevent infection and inhibition of immune activation with breakage of viral latency followed by vaccination should lead to an HIV-free generation.

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“…However, it is well-established that dysregulated production of cytokines/chemokines by several immune and nonimmune cell populations contributes to this process [6]. Among them, CCL2, TNF-a, and IL-1b have a prominent role in tissue damage and act as important modulators of HIV-1 replication [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…These signaling events are critical for the virus to promote its replication, establish a latent infection in CD4 + T cells, chronically activate the immune system, and hijack the signaling network shared among immune cells to facilitate viral pathogenesis [23,26,28, and reference therein]. In that context, deregulated immunometabolism is emerging as an important element contributing to the biased immunity against HIV-1 infection that leads to viral dissemination and pathogenesis [9,29,30]. Furthermore, growing evidence is accumulating on the importance of PLs, a group of enzymes catalyzing phospholipid cleavage, as key players in HIV-1 infection and host immune-metabolic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Phospholipases: at the crossroads of the immune system and the pathogenesis of HIV-1 infection

Cecchetti

Spadaro

Gessani

et al. 2016

Journal of Leukocyte Biology

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Multiple host factors and their interactions with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. The virus exploits the cell-signaling networks to prepare the ground for viral replication, to affect functions of either infected or uninfected bystander cells, and to evade the immune response. These events are hallmarks of HIV-1 pathogenesis that lead toward AIDS. Phospholipases are essential mediators of intracellular and intercellular signaling. They function as phospholipid-hydrolyzing enzymes, generating many bioactive lipid mediators or second messengers, which control multiple cellular functions, thus regulating a variety of physiologic and pathophysiologic processes. These enzymes also represent important components of the cell-signaling networks exploited by HIV-1 and its proteins to favor viral replication and persistence, as well as immune response dysfunction. Although some individual phospholipases were studied in the context of HIV-1 infection, the mechanisms whereby they regulate diverse infection-associated processes, as well as the interaction among different phospholipases have yet to be fully elucidated. In this review, we discuss the principal aspects of the complex interaction between phospholipases, HIV-1, and the immune system. A thorough understanding of the signaling networks that involve phospholipases in both HIV-1-infected cells and individuals is essential to determine whether therapeutic targeting of these enzymes may represent a novel approach to control viral replication, as well as the associated inflammation and comorbidities.

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Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects

Cited by 44 publications

References 148 publications

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

HIV immunotherapy comes of age: implications for prevention, treatment and cure

Phospholipases: at the crossroads of the immune system and the pathogenesis of HIV-1 infection

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