scholarly journals IL-15 regulates susceptibility of CD4+ T cells to HIV infection

2018 ◽  
Vol 115 (41) ◽  
pp. E9659-E9667 ◽  
Author(s):  
Lara Manganaro ◽  
Patrick Hong ◽  
Matthew M. Hernandez ◽  
Dionne Argyle ◽  
Lubbertus C. F. Mulder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Memory Cell ◽  
Viral Reservoir ◽  
Cell Infection ◽  
Hiv Reservoir ◽  
Sam Domain ◽  
Reservoir Stimulation ◽  
Immune Profiling

HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4+ memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established. Therefore, we investigated the molecular and cellular impact of IL-15 on CD4+ T-cell infection. We found that IL-15 stimulation induces SAM domain and HD domain-containing protein 1 (SAMHD1) phosphorylation due to cell cycle entry, relieving an early block to infection. Perturbation of the pathways downstream of IL-15 receptor (IL-15R) indicated that SAMHD1 phosphorylation after IL-15 stimulation is JAK dependent. Treating CD4+ T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15–induced SAMHD1 phosphorylation and protected CD4+ T cells from HIV infection. Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), we found that IL-15 stimulation altered the composition of CD4+ T-cell memory populations by increasing proliferation of memory CD4+ T cells, including CD4+ T memory stem cells (TSCM). IL-15–stimulated CD4+ TSCM, harboring phosphorylated SAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infection of CD4+ T cells with stem cell-like properties. Time-limited interventions with JAK1 inhibitors, such as Ruxolitinib, should prevent the inactivation of the endogenous restriction factor SAMHD1 and protect this long-lived CD4+ T-memory cell population from HIV infection.

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 FOXO1 promotes HIV Latency by suppressing ER stress in T cells

2020 ◽  
Author(s):  
Albert Vallejo-Gracia ◽  
Irene P. Chen ◽  
Rosalba Perrone ◽  
Emilie Besnard ◽  
Daniela Boehm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Er Stress ◽  
Viral Reservoir ◽  
Activated T Cells ◽  
Calcium Dependent ◽  
Cell Quiescence ◽  
Latently Infected ◽  
Latent Hiv

AbstractQuiescence is a hallmark of CD4+ T cells latently infected with HIV-1. While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. Here we report that FOXO1, a key regulator of T-cell quiescence, promotes latency and suppresses productive HIV infection. In resting T cells, FOXO1 inhibition induces ER stress and activates two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of PKR-like endoplasmic reticulum kinase (PERK), a known link between ER stress and ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppress HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a novel link between FOXO1, ER stress, and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.

scholarly journals Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques

2016 ◽  
Vol 90 (12) ◽  
pp. 5643-5656 ◽  
Author(s):  
Claudia R. Avalos ◽  
Sarah L. Price ◽  
Ellen R. Forsyth ◽  
Julia N. Pin ◽  
Erin N. Shirk ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Myeloid Cells ◽  
Viral Reservoir ◽  
Viral Genomes ◽  
Immunodeficiency Virus ◽  
Monocytes And Macrophages

ABSTRACTDespite the success of combined antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains a lifelong infection because of latent viral reservoirs in infected patients. The contribution of CD4+T cells to infection and disease progression has been extensively studied. However, during early HIV infection, macrophages in brain and other tissues are infected and contribute to tissue-specific diseases, such as encephalitis and dementia in brain and pneumonia in lung. The extent of infection of monocytes and macrophages has not been rigorously assessed with assays comparable to those used to study infection of CD4+T cells and to evaluate the number of CD4+T cells that harbor infectious viral genomes. To assess the contribution of productively infected monocytes and macrophages to HIV- and simian immunodeficiency virus (SIV)-infected cellsin vivo, we developed a quantitative virus outgrowth assay (QVOA) based on similar assays used to quantitate CD4+T cell latent reservoirs in HIV- and SIV-infected individuals in whom the infection is suppressed by ART. Myeloid cells expressing CD11b were serially diluted and cocultured with susceptible cells to amplify virus. T cell receptor β RNA was measured as a control to assess the potential contribution of CD4+T cells in the assay. Virus production in the supernatant was quantitated by quantitative reverse transcription-PCR. Productively infected myeloid cells were detected in blood, bronchoalveolar lavage fluid, lungs, spleen, and brain, demonstrating that these cells persist throughout SIV infection and have the potential to contribute to the viral reservoir during ART.IMPORTANCEInfection of CD4+T cells and their role as latent reservoirs have been rigorously assessed; however, the frequency of productively infected monocytes and macrophagesin vivohas not been similarly studied. Myeloid cells, unlike lymphocytes, are resistant to the cytopathic effects of HIV. Moreover, tissue-resident macrophages have the ability to self-renew and persist in the body for months to years. Thus, tissue macrophages, once infected, have the characteristics of a potentially stable viral reservoir. A better understanding of the number of productively infected macrophages is crucial to further evaluate the role of infected myeloid cells as a potential viral reservoir. In the study described here we compared the frequency of productively infected CD4+T cells and macrophages in an SIV-infected macaque model. We developed a critical assay that will allow us to quantitate myeloid cells containing viral genomes that lead to productive infection in SIV-infected macaques and assess the role of macrophages as potential reservoirs.

scholarly journals T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals

2021 ◽  
Vol 17 (4) ◽  
pp. e1009533
Author(s):  
Stefano Rinaldi ◽  
Lesley de Armas ◽  
Sara Dominguez-Rodríguez ◽  
Suresh Pallikkuth ◽  
Vinh Dinh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Viral Reservoir ◽  
Molecular Profile ◽  
Viral Control ◽  
Hiv Reservoir ◽  
Hiv Dna

The size of the latent HIV reservoir is associated with the timing of therapeutic interventions and overall health of the immune system. Here, we demonstrate that T cell phenotypic signatures associate with viral reservoir size in a cohort of HIV vertically infected children and young adults under durable viral control, and who initiated anti-retroviral therapy (ART) <2 years old. Flow cytometry was used to measure expression of immune activation (IA), immune checkpoint (ICP) markers, and intracellular cytokine production after stimulation with GAG peptides in CD4 and CD8 T cells from cross-sectional peripheral blood samples. We also evaluated the expression of 96 genes in sort-purified total CD4 and CD8 T cells along with HIV-specific CD4 and CD8 T cells using a multiplexed RT-PCR approach. As a measure of HIV reservoir, total HIV-DNA quantification by real-time PCR was performed. Poisson regression modeling for predicting reservoir size using phenotypic markers revealed a signature that featured frequencies of PD-1+CD4 T cells, TIGIT+CD4 T cells and HIV-specific (CD40L+) CD4 T cells as important predictors and it also shows that time of ART initiation strongly affects their association with HIV-DNA. Further, gene expression analysis showed that the frequencies of PD-1+CD4 T cells associated with a CD4 T cell molecular profile skewed toward an exhausted Th1 profile. Our data provide a link between immune checkpoint molecules and HIV persistence in a pediatric cohort as has been demonstrated in adults. Frequencies of PD-1+ and TIGIT+CD4 T cells along with the frequency of HIV-specific CD4 T cells could be associated with the mechanism of viral persistence and may provide insight into potential targets for therapeutic intervention.

scholarly journals An HIV-induced mechanism for T cell quiescence and proviral latency

2021 ◽  
Author(s):  
Saba Valadkhan ◽  
Leah Plasek ◽  
Lalith Gunawardane ◽  
Farshad Niazi ◽  
Sara Mason ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cellular Proliferation ◽  
Latent Reservoir ◽  
Hiv Reservoir ◽  
P53 Signaling ◽  
Cell Quiescence ◽  
Latent Hiv ◽  
Sporadic Infection

Abstract HIV persists in infected individuals despite effective antiretroviral therapy due to the rapid establishment of a latent HIV reservoir, mainly composed of quiescent memory CD4+ T cells1–3. The mechanisms governing the formation of the latent reservoir remain poorly understood. It is commonly assumed that entry of HIV into latency is a rare and random event associated with sporadic infection of effector T-cells transitioning to a memory phenotype4–8. Using human primary CD4+ T cell models, we show instead, that HIV infection itself triggers a strong transcriptomic remodeling that results in activation of a quiescence program, including downregulation of cellular proliferation and metabolic pathways. This transcriptional program is initiated by KLF2, a key regulator of quiescence, along with activation of the p53 pathway and downregulation of MYC. Loss and gain of function studies confirmed that KLF2 and p53 signaling are responsible for the downregulation of MYC and proliferation pathways, and consequently, proviral transcriptional silencing. Thus, HIV infection per se, enhances the formation of the latent reservoir in T-cells, ensuring viral persistence in infected individuals. These findings identify a new and unexpected mechanism for the formation of the latent HIV reservoir, and broaden the repertoire of strategies through which viruses can control the host cell to their advantage.

scholarly journals Significant Depletion of CD4+T Cells Occurs in the Oral Mucosa during Simian Immunodeficiency Virus Infection with the Infected CD4+T Cell Reservoir Continuing to Persist in the Oral Mucosa during Antiretroviral Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jeffy George ◽  
Wendeline Wagner ◽  
Mark G. Lewis ◽  
Joseph J. Mattapallil
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Simian Immunodeficiency Virus ◽  
Oral Mucosa ◽  
Mucosal Immunity ◽  
Viral Reservoir ◽  
Long Term Outcome ◽  
Immunodeficiency Virus ◽  
A Minor

Human and simian immunodeficiency virus (HIV and SIV) infections are characterized by manifestation of numerous opportunistic infections and inflammatory conditions in the oral mucosa. The loss of CD4+T cells that play a critical role in maintaining mucosal immunity likely contributes to this process. Here we show that CD4+T cells constitute a minor population of T cells in the oral mucosa and display a predominantly central memory phenotype mirroring other mucosal sites such as the rectal mucosa. Chronic SIV infection was associated with a near total depletion of CD4+T cells in the oral mucosa that appear to repopulate during antiretroviral therapy (ART). Repopulating CD4+T cells harbored a large fraction of Th17 cells suggesting that ART potentially reconstitutes oral mucosal immunity. However, a minor fraction of repopulating CD4+T cells harbored SIV DNA suggesting that the viral reservoir continues to persist in the oral mucosa during ART. Therapeutic approaches aimed at obtaining sustainable CD4+T cell repopulation in combination with strategies that can eradicate the latent viral reservoir in the oral mucosa are essential for better oral health and long-term outcome in HIV infected patients.

186 Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A200-A200
Author(s):  
Yuki Muroyama ◽  
Yuki Muroyama ◽  
Sasikanth Manne ◽  
Alexandar Huang ◽  
Divij Mathew ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Endometrial Cancer ◽  
T Cell ◽  
Clinical Response ◽  
Cancer Patients ◽  
T Cell Response ◽  
High Dimensional ◽  
Uterine Endometrial Cancer ◽  
Immune Profiling

BackgroundAlthough immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite instability (MSIHI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors.MethodsTo dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery.ResultsChemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab had a proliferative T cell response 2–4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells are enriched in responders, whereas early expansion Tregs are enriched in non-responders. Unlike patients with uterine endometrial cancer, patients with TMBlo ovarian cancer did not have a clear proliferative CD8 T cell response after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression. At baseline, ovarian cancer without recurrence have more terminally differentiated effector-like CD8 T cells, and patients with recurrence have more naive-like cells. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-H uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration post immunotherapy and clinical response. This suggests the importance of optimize therapeutic timing to maximize the therapeutic efficacy when combining immunotherapy and chemotherapy.ConclusionsCollectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that TMBhi inflamed versus TMBlo cold tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 and 17–182.

Increases in T Cell Telomere Length in HIV Infection after Antiretroviral Combination Therapy for HIV-1 Infection Implicate Distinct Population Dynamics in CD4+ and CD8+ T Cells

1999 ◽  
Vol 92 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Sumesh Kaushal ◽  
Alan L. Landay ◽  
Michael M. Lederman ◽  
Elizabeth Connick ◽  
John Spritzler ◽  
...  
Keyword(s):  
T Cells ◽  
Population Dynamics ◽  
T Cell ◽  
Combination Therapy ◽  
Hiv Infection ◽  
Telomere Length ◽  
Cd8 T Cells ◽  
Distinct Population ◽  
Hiv 1

scholarly journals CD4+CD8+T Cells Represent a Significant Portion of the Anti-HIV T Cell Response to Acute HIV Infection

2012 ◽  
Vol 188 (9) ◽  
pp. 4289-4296 ◽  
Author(s):  
Marc A. Frahm ◽  
Ralph A. Picking ◽  
JoAnn D. Kuruc ◽  
Kara S. McGee ◽  
Cynthia L. Gay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cell Response ◽  
T Cell Response ◽  
Acute Hiv Infection ◽  
Acute Hiv ◽  
Anti Hiv

scholarly journals Selective anergy of V beta 8+ T cells in human immunodeficiency virus-infected individuals.

1994 ◽  
Vol 179 (2) ◽  
pp. 413-424 ◽  
Author(s):  
G Dadaglio ◽  
S Garcia ◽  
L Montagnier ◽  
M L Gougeon
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Clinical Status ◽  
Interleukin 2 ◽  
Cell Subset ◽  
T Cell Subset ◽  
Immunodeficiency Virus

We have analyzed the V beta usage by CD4+ and CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals in response to an in vitro stimulation with the superantigenic erythrogenic toxin A (ETA) of Streptococcus pyogenes. ETA amplifies specifically CD4+ and CD8+ T cells from control donors expressing the V beta 8 and the V beta 12 elements. When peripheral T cells from asymptomatic HIV-infected individuals were stimulated with ETA, there was a complete lack of activation of the V beta 8+ T cell subset, whereas the V beta 12+ T cell subset responded normally to the superantigen. This V beta-specific anergy, which was also observed in response to staphylococcal enterotoxin E (SEE), affected both CD4+ and CD8+ T cells and represented an intrinsic functional defect rather than a specific lack of response to bacterial superantigens since it was also observed after a stimulation with V beta 8 monoclonal antibodies. The V beta 8 anergic T cells did not express interleukin 2 receptors (IL-2Rs) and failed to proliferate in response to exogenous IL-2 or IL-4, suggesting that this anergy was not a reversible process, at least by the use of these cytokines. The unresponsiveness of the V beta 8 T cell subset is frequent since it was found in 56% of the patients studied, and comparison of the clinical status of responder vs. anergic patients indicated that the only known common factor between them was HIV infection. In addition, it is noteworthy that the anergy of the V beta 8 subset may be a very early phenomenon since it was found in a patient at Centers for Disease Control stage I of the disease. These data provide evidence that a dominant superantigen may be involved in the course of HIV infection and that the contribution of HIV has to be considered.

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