HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4<sup>+</sup> T cell death

Daussy, Coralie F.; Galais, Mathilde; Pradel, Baptiste; Robert-Hebmann, Véronique; Sagnier, Sophie; Pattingre, Sophie; Biard-Piechaczyk, Martine; Espert, Lucile

doi:10.1080/15548627.2020.1831814

Cited by 22 publications

(22 citation statements)

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“…The HIV life cycle could end with cell death of infected cells or by HIV-1 Env-mediated cell death of uninfected bystander cells (Mohammadi et al, 2013;Cummins and Badley, 2014;Doitsh and Greene, 2016;Li et al, 2020) which occurs during early infection (Espert et al, 2008(Espert et al, , 2009. Hence, one of the most relevant HIV-1 modulators of cell death is the Env glycoprotein (Krüger et al, 1996;Blanco et al, 2001;Vlahakis et al, 2001;Blumenthal, 2006, 2008;Varbanov et al, 2006;Garg et al, 2009;Sivaraman et al, 2009;Gorry and Ancuta, 2011;Cicala et al, 2016;Joshi et al, 2016;Tsao et al, 2016;Evering, 2018;Daussy et al, 2020).…”

Section: The Role Of Autophagy In the Early Steps Of Hiv-1 Infectionmentioning

confidence: 99%

“…Furthermore, after contact between CD4 + T lymphocytes and Env-expressing cells, reactive oxygen species (ROS) are accumulated and its production is known to be involved in autophagy (Molina et al, 2007;Borel et al, 2012). It has recently been reported that peroxisomes, organelles involved in the control of oxidative stress, are targeted by Env-mediated autophagy, inducing oxidative stress and this leads to uninfected CD4 + T cells death (Daussy et al, 2020).…”

Section: Hiv-1 Env-mediated Regulation Of Autophagy and Related Factors During Early Infection In T Lymphocytesmentioning

confidence: 99%

“…Related to the above deadly autophagy activation by HIV-1 Env, it has been reported that viral Env activates peroxisome degradation with a concomitant decrease in the expression of peroxisomal proteins [i.e., CAT (catalase) and PEX14 (peroxisomal biogenesis factor 14; also named peroxin 14)], which appears to be autophagy dependent, since down-regulation of BECN1 and SQSTM1/p62 restores their expression levels (Daussy et al, 2020). It is noteworthy that late autophagy occurrence is reported to be independent of the HIV-1 infected phenotype, VNP or RP, but it strongly correlated with the fusogenic capacity of viral Envs (Cabrera-Rodriguez et al, 2019).…”

Section: Hiv-1 Env Modulates Autophagy and Related Factors Associated With Membrane And Cytoskeleton Dynamics Key Events For Productive Ementioning

confidence: 99%

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The Interplay of HIV and Autophagy in Early Infection

et al. 2021

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HIV/AIDS is still a global threat despite the notable efforts made by the scientific and health communities to understand viral infection, to design new drugs or to improve existing ones, as well as to develop advanced therapies and vaccine designs for functional cure and viral eradication. The identification and analysis of HIV-1 positive individuals that naturally control viral replication in the absence of antiretroviral treatment has provided clues about cellular processes that could interact with viral proteins and RNA and define subsequent viral replication and clinical progression. This is the case of autophagy, a degradative process that not only maintains cell homeostasis by recycling misfolded/old cellular elements to obtain nutrients, but is also relevant in the innate and adaptive immunity against viruses, such as HIV-1. Several studies suggest that early steps of HIV-1 infection, such as virus binding to CD4 or membrane fusion, allow the virus to modulate autophagy pathways preparing cells to be permissive for viral infection. Confirming this interplay, strategies based on autophagy modulation are able to inhibit early steps of HIV-1 infection. Moreover, autophagy dysregulation in late steps of the HIV-1 replication cycle may promote autophagic cell-death of CD4+ T cells or control of HIV-1 latency, likely contributing to disease progression and HIV persistence in infected individuals. In this scenario, understanding the molecular mechanisms underlying HIV/autophagy interplay may contribute to the development of new strategies to control HIV-1 replication. Therefore, the aim of this review is to summarize the knowledge of the interplay between autophagy and the early events of HIV-1 infection, and how autophagy modulation could impair or benefit HIV-1 infection and persistence, impacting viral pathogenesis, immune control of viral replication, and clinical progression of HIV-1 infected patients.

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Section: The Role Of Autophagy In the Early Steps Of Hiv-1 Infectionmentioning

confidence: 99%

Section: Hiv-1 Env-mediated Regulation Of Autophagy and Related Factors During Early Infection In T Lymphocytesmentioning

confidence: 99%

Section: Hiv-1 Env Modulates Autophagy and Related Factors Associated With Membrane And Cytoskeleton Dynamics Key Events For Productive Ementioning

confidence: 99%

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The Interplay of HIV and Autophagy in Early Infection

et al. 2021

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“…This interconnection might be relevant, as we recently showed that HIV-1 infection leads to enhancement of antioxidant defenses in primary CD4 + T-cells (Shytaj et al, 2020). HIV-1 infection causes an initial oxidative stress (Daussy et al, 2020), which then leads to the nuclear translocation of the master antioxidant transcription factor Nrf2. This translocation in turn induces transcription of several proteins involved in antioxidant response, including glucose 6-phosphate dehydrogenase (G6PDH), which diverts glucose 6-phosphate from the glycolytic pathway to the pentose cycle, responsible for production of the antioxidant NADPH.…”

Section: Introductionmentioning

confidence: 94%

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Shytaj

Procopio

Tarek

et al. 2020

Preprint

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HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic and metabolomic analysis, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, the antioxidant NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people-living-with-HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

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“…A study showed that expression of HIV viral envelope glycoproteins (Env) triggers massive macroautophagy/autophagy as well as pexophagy, which results in the elimination of mature peroxisomes in CD4 + T cells. In addition, Env expression induces a dramatic increase in cellular ROS, which induces cell death [ 80 ]. The study suggested that reducing the number of functional peroxisome through pexophagy may enhance oxidative stress, which can damage CD4 + T cells and contribute to the acquired immunodeficiency observed in HIV-1-infected patients.…”

Section: Roles Of Pexophagy In Health and Diseasementioning

confidence: 99%

Mechanisms and Functions of Pexophagy in Mammalian Cells

Wang

2021

Cells

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Peroxisomes play essential roles in diverse cellular metabolism functions, and their dynamic homeostasis is maintained through the coordination of peroxisome biogenesis and turnover. Pexophagy, selective autophagic degradation of peroxisomes, is a major mechanism for removing damaged and/or superfluous peroxisomes. Dysregulation of pexophagy impairs the physiological functions of peroxisomes and contributes to the progression of many human diseases. However, the mechanisms and functions of pexophagy in mammalian cells remain largely unknown compared to those in yeast. This review focuses on mammalian pexophagy and aims to advance the understanding of the roles of pexophagy in human health and diseases. Increasing evidence shows that ubiquitination can serve as a signal for pexophagy, and ubiquitin-binding receptors, substrates, and E3 ligases/deubiquitinases involved in pexophagy have been described. Alternatively, pexophagy can be achieved in a ubiquitin-independent manner. We discuss the mechanisms of these ubiquitin-dependent and ubiquitin-independent pexophagy pathways and summarize several inducible conditions currently used to study pexophagy. We highlight several roles of pexophagy in human health and how its dysregulation may contribute to diseases.

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HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4⁺ T cell death

Cited by 22 publications

References 64 publications

The Interplay of HIV and Autophagy in Early Infection

The Interplay of HIV and Autophagy in Early Infection

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Mechanisms and Functions of Pexophagy in Mammalian Cells

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HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4+ T cell death

Cited by 22 publications

References 64 publications

The Interplay of HIV and Autophagy in Early Infection

The Interplay of HIV and Autophagy in Early Infection

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Mechanisms and Functions of Pexophagy in Mammalian Cells

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HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4⁺ T cell death