scholarly journals Virion encapsidated HIV-1 Vpr induces NFAT to prime non-activated T cells for productive infection

Open Biology ◽  
2016 ◽  
Vol 6 (7) ◽  
pp. 160046 ◽  
Author(s):  
Kristin Höhne ◽  
Ramona Businger ◽  
Anouk van Nuffel ◽  
Sebastian Bolduan ◽  
Herwig Koppensteiner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Productive Infection ◽  
Cell Infection ◽  
Viral Reservoirs ◽  
Activated T Cells ◽  
Cycle Arrest ◽  
Nfat Activation ◽  
Mediate Cell ◽  
Hiv 1

The majority of T cells encountered by HIV-1 are non-activated and do not readily allow productive infection. HIV-1 Vpr is highly abundant in progeny virions, and induces signalling and HIV-1 LTR transcription. We hence hypothesized that Vpr might be a determinant of non-activated T-cell infection. Virion-delivered Vpr activated nuclear factor of activated T cells (NFAT) through Ca 2+ influx and interference with the NFAT export kinase GSK3β. This leads to NFAT translocation and accumulation within the nucleus and was required for productive infection of unstimulated primary CD4 + T cells. A mutagenesis approach revealed correlation of Vpr-mediated NFAT activation with its ability to enhance LTR transcription and mediate cell cycle arrest. Upon NFAT inhibition, Vpr did not augment resting T-cell infection, and showed reduced G2/M arrest and LTR transactivation. Altogether, Vpr renders unstimulated T cells more permissive for productive HIV-1 infection and stimulates activation of productively infected as well as virus-exposed T cells. Therefore, it could be involved in the establishment and reactivation of HIV-1 from viral reservoirs and might have an impact on the levels of immune activation, which are determinants of HIV-1 pathogenesis.

scholarly journals Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection

2021 ◽  
Vol 17 (12) ◽  
pp. e1010105
Author(s):  
Vishakha Sharma ◽  
Matthew Creegan ◽  
Andrey Tokarev ◽  
Denise Hsu ◽  
Bonnie M. Slike ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebrospinal Fluid ◽  
T Cell ◽  
Viral Rna ◽  
Cd4 T Cell ◽  
Cell Infection ◽  
Viral Reservoirs ◽  
Acute Hiv ◽  
Shiv Infection ◽  
Hiv 1

HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus. We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6; Fiebig III/IV). Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies.

scholarly journals Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

2005 ◽  
Vol 79 (5) ◽  
pp. 3195-3199 ◽  
Author(s):  
Jean-Daniel Lelièvre ◽  
Frédéric Petit ◽  
Damien Arnoult ◽  
Jean-Claude Ameisen ◽  
Jérôme Estaquier
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Infection ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

scholarly journals Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

2008 ◽  
Vol 2 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Naveed Gulzar ◽  
Sowyma Balasubramanian ◽  
Greg Harris ◽  
Jaime Sanchez-Dardon ◽  
Karen F.T. Copeland
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Proliferative Response ◽  
Cell Infection ◽  
Cellular Target ◽  
Potential Reservoir ◽  
Infected Cells ◽  
Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

Regulation of nuclear factor of activated T cells by phosphotyrosyl-specific phosphatase activity: a positive effect on HIV-1 long terminal repeat–driven transcription and a possible implication of SHP-1

Blood ◽  
2001 ◽  
Vol 97 (8) ◽  
pp. 2390-2400 ◽  
Author(s):  
Jean-François Fortin ◽  
Benoit Barbeau ◽  
Gilles A. Robichaud ◽  
Marie-Ève Paré ◽  
Anne-Marie Lemieux ◽  
...  
Keyword(s):  
T Cells ◽  
Long Terminal Repeat ◽  
Nuclear Translocation ◽  
Interleukin 2 ◽  
Dominant Negative ◽  
Terminal Repeat ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Nfat Activation ◽  
Hiv 1

Abstract Although protein tyrosine phosphatase (PTP) inhibitors used in combination with other stimuli can induce interleukin 2 (IL-2) production in T cells, a direct implication of nuclear factor of activated T cells (NFAT) has not yet been demonstrated. This study reports that exposure of leukemic T cells and human peripheral blood mononuclear cells to bis-peroxovanadium (bpV) PTP inhibitors markedly induce activation and nuclear translocation of NFAT. NFAT activation by bpV was inhibited by the immunosuppressive drugs FK506 and cyclosporin A, as well as by a specific peptide inhibitor of NFAT activation. Mobility shift assays showed specific induction of the NFAT1 member by bpV molecules. The bpV-mediated NFAT activation was observed to be important for the up-regulation of the human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) and the IL-2 promoter; NFAT1 was demonstrated to be particularly important in bpV-dependent positive action on HIV-1 LTR transcription. The active participation of p56lck, ZAP-70, p21ras, and calcium in the bpV-mediated signaling cascade leading to NFAT activation was confirmed, using deficient cell lines and dominant-negative mutants. Finally, overexpression of wild-type SHP-1 resulted in a greatly diminished activation of NFAT by bpV, suggesting an involvement of SHP-1 in the regulation of NFAT activation. These data were confirmed by constitutive NFAT translocation observed in Jurkat cells stably expressing a dominant-negative version of SHP-1. The study proposes that PTP activity attenuates constitutive kinase activities that otherwise would lead to constant NFAT activation and that this activation is participating in HIV-1 LTR stimulation by PTP inhibition.

scholarly journals Human T-Cell Lymphotropic Virus Type 1 p12I Expression Increases Cytoplasmic Calcium To Enhance the Activation of Nuclear Factor of Activated T Cells

2002 ◽  
Vol 76 (20) ◽  
pp. 10374-10382 ◽  
Author(s):  
Wei Ding ◽  
Björn Albrecht ◽  
Robert E. Kelley ◽  
Natarajan Muthusamy ◽  
Seung-Jae Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Calcium Release ◽  
Nuclear Factor ◽  
Cytoplasmic Calcium ◽  
Activated T Cells ◽  
Human T Cell ◽  
Nfat Activation

ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) establishes persistent infection and is associated with lymphoproliferative or neurodegenerative diseases. As a complex retrovirus, HTLV-1 contains typical structural and enzymatic genes, as well as regulatory and accessory genes encoded in the pX region. The early events necessary for HTLV-1 to establish infection in lymphocytes, its primary target cells, remain unresolved. Recent studies have demonstrated the importance of regulatory and accessory gene products in determining this virus-host interaction. Among these, pX open reading frame I, which encodes two proteins, p12I and p27I, is required for establishing persistent infection in vivo and for infection in quiescent primary lymphocytes. In addition, p12I localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus and associates with a calcium binding protein, calreticulin. We recently reported that p12I expression induces the calcium-responsive T-cell transcription factor, nuclear factor of activated T cells (NFAT), in the presence of phorbol ester activation. Based on these studies, we hypothesize that p12I may modulate calcium release from the ER. Here, we report that p12I expression increases basal cytoplasmic calcium and concurrently diminishes calcium available for release from the ER stores. Overexpression of calreticulin, a calcium buffer protein, blocked p12I-mediated NFAT activation independently of its ability to bind p12I. Chemical inhibition studies using inhibitors of inositol 1,4,5-triphosphate receptor and calcium release-activated calcium channels suggest that inositol 1,4,5-triphosphate receptor in the ER membrane and calcium release-activated calcium channels in the plasma membrane contribute to p12I-mediated NFAT activation. Collectively, our results are the first to demonstrate the role of p12I in elevating cytoplasmic calcium, an antecedent to T-cell activation, and further support the important role of this accessory protein in the early events of HTLV-1 infection.

scholarly journals Calcitonin gene–related peptide inhibits Langerhans cell–mediated HIV-1 transmission

2013 ◽  
Vol 210 (11) ◽  
pp. 2161-2170 ◽  
Author(s):  
Yonatan Ganor ◽  
Anne-Sophie Drillet-Dangeard ◽  
Lucia Lopalco ◽  
Daniela Tudor ◽  
Giuseppe Tambussi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Highly Active Antiretroviral Therapy ◽  
Plasma Levels ◽  
Calcitonin Gene Related Peptide ◽  
Cell Infection ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Hiv 1

Upon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene–related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC–T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1–infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1.

scholarly journals HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines

2015 ◽  
Vol 90 (2) ◽  
pp. 904-916 ◽  
Author(s):  
Benjamin Trinité ◽  
Chi N. Chan ◽  
Caroline S. Lee ◽  
David N. Levy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Reverse Transcription ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Productive Infection ◽  
Hiv 1

ABSTRACTHIV-1 infection leads to the progressive depletion of the CD4 T cell compartment by various known and unknown mechanisms.In vivo, HIV-1 infects both activated and resting CD4 T cells, butin vitro, in the absence of any stimuli, resting CD4 T cells from peripheral blood are resistant to infection. This resistance is generally attributed to an intracellular environment that does not efficiently support processes such as reverse transcription (RT), resulting in abortive infection. Here, we show thatin vitroHIV-1 infection of resting CD4 T cells induces substantial cell death, leading to abortive infection.In vivo, however, various microenvironmental stimuli in lymphoid and mucosal tissues provide support for HIV-1 replication. For example, common gamma-chain cytokines (CGCC), such as interleukin-7 (IL-7), render resting CD4 T cells permissible to HIV-1 infection without inducing T cell activation. Here, we find that CGCC primarily allow productive infection by preventing HIV-1 triggering of apoptosis, as evidenced by early release of cytochromecand caspase 3/7 activation. Cell death is triggered both by products of reverse transcription and by virion-borne Vpr protein, and CGCC block both mechanisms. When HIV-1 RT efficiency was enhanced by SIVmac239 Vpx protein, cell death was still observed, indicating that the speed of reverse transcription and the efficiency of its completion contributed little to HIV-1-induced cell death in this system. These results show that a major restriction on HIV-1 infection in resting CD4 T cells resides in the capacity of these cells to survive the early steps of HIV-1 infection.IMPORTANCEA major consequence of HIV-1 infection is the destruction of CD4 T cells. Here, we show that delivery of virion-associated Vpr protein and the process of reverse transcription are each sufficient to trigger apoptosis of resting CD4 T cells isolated from peripheral blood. While these 2 mechanisms have been previously described in various cell types, we show for the first time their concerted effect in inducing resting CD4 T cell depletion. Importantly, we found that cytokines such as IL-7 and IL-4, which are particularly active in sites of HIV-1 replication, protect resting CD4 T cells from these cytopathic effects and, primarily through this protection, rather than through enhancement of specific replicative steps, they promote productive infection. This study provides important new insights for the understanding of the early steps of HIV-1 infection and T cell depletion.

Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4660-4663 ◽  
Author(s):  
Fedde Groot ◽  
Sonja Welsch ◽  
Quentin J. Sattentau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Human Monocyte ◽  
Productive Infection ◽  
Virological Synapse ◽  
Primary Target ◽  
Virological Synapses ◽  
Adhesive Contacts ◽  
Hiv 1

Abstract Macrophages are reservoirs of HIV-1 infection, proposed to transmit virus to CD4+ T cells, the primary target of the virus. Here we report that human monocyte-derived macrophages (MDMs) rapidly spread HIV-1 to autologous CD4+ T cells resulting in productive infection. Transmission takes place across transient adhesive contacts between T cells and MDMs, which have the features of a virological synapse including copolarization of CD4 on the T cell with HIV-1 Gag and Env on the macrophage. We propose that an infected MDM can infect at least one T cell every 6 hours. Since HIV-1–infected macrophages can survive for many weeks, these results highlight the central role played by macrophages in HIV-1 infection and pathogenesis.

scholarly journals HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

2021 ◽  
Author(s):  
Ann-Kathrin Reuschl ◽  
Maitreyi Shivkumar ◽  
Dejan Mesner ◽  
Laura J. Pallett ◽  
José Afonso Guerra-Assunção ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Biology ◽  
Memory T Cells ◽  
Virus Production ◽  
Cell Loss ◽  
Productive Infection ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) replicates in CD4+ T cells leading to profound T cell loss, immunological dysfunction and AIDS. Determining how HIV-1 shapes the immunological niche in which it resides to create a permissive environment is central to informing efforts to limit pathogenesis, disturb viral reservoirs and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate CD4+ T cells in vitro in order to make them permissive to infection. This dramatically alters T cell biology, obscuring native virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient and productive infection of resting CD4+ T cells without the need for prior activation. Infection is preferential for resting memory T cells, is observed with both CXCR4-tropic virus and CCR5-tropic transmitter-founder viruses and results in virus production and onward spreading infection. Strikingly, we find that HIV-1 infection of resting memory CD4+ T cells primes for induction of a tissue-resident memory (TRM)-like phenotype evidenced by upregulation of TRM markers CD69/CXCR6 alongside co-expression of CD49a, PD-1, CD101 as well as transcription factor Blimp-1. Furthermore, we reveal that HIV-1 initiates a transcriptional program that overlaps with the core TRM transcriptional signature. This reprograming depends on the HIV-1 accessory protein Vpr. We propose that HIV-1 infection drives a CD4+ TRM-phenotype potentially sequestering infected cells within tissues to support viral replication and persistence.

scholarly journals Curcumin Suppresses T Cell Activation by Blocking Ca 2+ Mobilization and Nuclear Factor of Activated T Cells (NFAT) Activation

2012 ◽  
Vol 287 (13) ◽  
pp. 10200-10209 ◽  
Author(s):  
Christian Kliem ◽  
Anette Merling ◽  
Marco Giaisi ◽  
Rebecca Köhler ◽  
Peter H. Krammer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Nfat Activation
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