scholarly journals HIV: Persistence through division

2017 ◽  
Vol 214 (4) ◽  
pp. 875-876 ◽  
Author(s):  
Lillian B. Cohn ◽  
Michel C. Nussenzweig
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Proliferation ◽  
Latent Reservoir ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Hiv 1

A long-lived latent reservoir for HIV-1 persists in CD4+ T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir.

Decreased HIV-specific CD4 T cell proliferation in long-term HIV-infected individuals on antiretroviral therapy

AIDS ◽  
2001 ◽  
Vol 15 (14) ◽  
pp. 1885-1887 ◽  
Author(s):  
Smita A. Ghanekar ◽  
Sharon A. Stranford ◽  
June C. Ong ◽  
Joshua M. Walker ◽  
Vernon C. Maino ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cd4 T Cell ◽  
T Cell Proliferation

scholarly journals The Unenlarged Lymph Nodes of HIV-1–infected, Asymptomatic Patients with High CD4 T Cell Counts Are Sites for Virus Replication and CD4 T Cell Proliferation. The Impact of Highly Active Antiretroviral Therapy

1998 ◽  
Vol 187 (6) ◽  
pp. 949-959 ◽  
Author(s):  
Klara Tenner-Racz ◽  
Hans-Jürgen Stellbrink ◽  
Jan van Lunzen ◽  
Claus Schneider ◽  
Jan-Peter Jacobs ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Immune System ◽  
Drug Therapy ◽  
T Cell ◽  
Lymph Nodes ◽  
Lymphoid Tissue ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Hiv 1

The efficacy of triple drug therapy for HIV-1 infection encourages its early use to prevent damage to the immune system. We monitored the effects of such therapy on 12 patients with 14–75-mo histories of minimal disease, i.e., CD4+ counts constantly >500/μl and little or no lymph node enlargement. In this way, we could first determine the extent of viral replication and immunoarchitectural changes in unenlarged nodes early in disease, and second follow the response to triple therapy in plasma and lymphoid tissue in tandem. As is known for lymph nodes with more advanced disease, the germinal centers showed productively infected T cells, i.e., CD4+CD1a−CD68− cells labeling intensely for HIV-1 RNA after in situ hybridization. The unenlarged nodes also showed extensive HIV-1 RNA retention on a well-preserved, follicular dendritic cell (FDC) network, and the follicles were abnormal. There were numerous CD8+ cells, many expressing TIA-1 granule antigen. Also, in contrast to normal follicles, CD4+ T cell proliferation was active, with marked increases in the number of cycling, Ki-67+CD4+CD45R0+ cells. After 28 d and 3 mo of therapy, productively infected T cells decreased dramatically and often were not apparent. The labeling of the FDC network for viral RNA also decreased, but not for gag protein. We conclude that HIV-1 replicates and accumulates in lymphoid organs before damage of the immune system, that at this stage of disease de novo production of T cells occurs in the lymphoid tissue, and that the infection is sensitive to triple drug therapy in both plasma and lymph nodes.

T Cell Proliferation and Apoptosis in HIV-1-Infected Lymphoid Tissue: Impact of Highly Active Antiretroviral Therapy

2001 ◽  
Vol 101 (2) ◽  
pp. 180-191 ◽  
Author(s):  
Anne Ma Dyrhol-Riise ◽  
Maria Ohlsson ◽  
Kathrine Skarstein ◽  
Svein J.T. Nygaard ◽  
Jan Olofsson ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Lymphoid Tissue ◽  
T Cell Proliferation ◽  
Highly Active ◽  
Proliferation And Apoptosis ◽  
Hiv 1

scholarly journals OA031-02. Regulatory T cells inhibit CD8 T cell proliferation in HIV-1 infection through CD39/adenosine pathway

Retrovirology ◽  
2009 ◽  
Vol 6 (Suppl 3) ◽  
pp. O20 ◽  
Author(s):  
M Nikolova ◽  
M Carriere ◽  
J Lelievre ◽  
M Muhtarova ◽  
A Bensussan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cell ◽  
T Cell Proliferation ◽  
Hiv 1

scholarly journals HIV-1 Persistence in Children during Suppressive ART

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1134
Author(s):  
Mary Grace Katusiime ◽  
Gert U. Van Zyl ◽  
Mark F. Cotton ◽  
Mary F. Kearney
Keyword(s):  
Antiretroviral Therapy ◽  
Early Life ◽  
Clonal Expansion ◽  
Hiv Cure ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Increased Risk ◽  
Infected Cells ◽  
Hiv 1

There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure.

scholarly journals Nonradioactive Techniques for Measurement of In Vitro T-Cell Proliferation: Alternatives to the [3H]Thymidine Incorporation Assay

2000 ◽  
Vol 7 (4) ◽  
pp. 687-692 ◽  
Author(s):  
Tsehaynesh Messele ◽  
Marijke T. L. Roos ◽  
Dorte Hamann ◽  
Maarten Koot ◽  
Arnaud L. Fontanet ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Alternative Methods ◽  
Brdu Incorporation ◽  
T Cell Proliferation ◽  
Proliferative Capacity ◽  
Cd38 Expression ◽  
Hiv 1

ABSTRACT T-cell proliferation is an important in vitro parameter of in vivo immune function and has been used as a prognostic marker of human immunodeficiency virus type 1 (HIV-1) disease progression. The proliferative capacity of T cells in response to various stimuli is commonly determined by a radioactive assay based on incorporation of [3H]thymidine ([3H]TdR) into newly generated DNA. In order to assess techniques for application in laboratories where radioactive facilities are not present, two alternative methods were tested and compared to the [3H]TdR assay as a “gold standard.” As an alternative, T-cell proliferation was measured by flow cytometric assessment of CD38 expression on T cells and by an enzyme-linked immunosorbent assay (ELISA) based on bromo-2′-deoxyuridine (BrdU) incorporation. Peripheral blood mononuclear cells (PBMCs), either in whole blood or Ficoll-Isopaque separated, from a total of 26 HIV-1-positive and 18 HIV-1-negative Dutch individuals were stimulated with CD3 monoclonal antibody (MAb) alone, a combination of CD3 and CD28 MAbs, or phytohemagglutinin. BrdU incorporation after 3 days of stimulation with a combination of CD3 and CD28 MAbs correlated excellently with the [3H]TdR incorporation in both study groups (HIV-1 positives, r = 0.96; HIV-1 negatives,r = 0.83). A significant correlation of absolute numbers of T cells expressing CD38 with [3H]TdR incorporation, both in HIV-1-positive (r = 0.96) and HIV-1-negative (r = 0.84) individuals, was also observed under these conditions. The results of this study indicate that determination of both the number of CD38-positive T cells and BrdU incorporation can be used as alternative techniques to measure the in vitro T-cell proliferative capacity. The measurement of CD38 expression on T cells provides the additional possibility to further characterize the proliferating T-cell subsets for expression of other surface markers.

scholarly journals CD161+ CD4+ T Cells Harbor Clonally Expanded Replication-Competent HIV-1 in Antiretroviral Therapy-Suppressed Individuals

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Xiaomin Li ◽  
Zhaoli Liu ◽  
Qijuan Li ◽  
Ronglin Hu ◽  
Lu Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Clonal Expansion ◽  
Latent Reservoir ◽  
Term Stability ◽  
Long Term Stability ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The presence of an extremely stable latent reservoir of HIV-1 is the major obstacle to eradication, despite effective antiretroviral therapy (ART). Recent studies have shown that clonal expansion of latently infected cells without viral reactivation is an important phenomenon that maintains the long-term stability of the reservoir, yet its underlying mechanism remains unclear. Here we report that a subset of CD4+ T cells, characterized by CD161 expression on the surface, is highly permissive for HIV-1 infection. These cells possess a significantly higher survival and proliferative capacity than their CD161-negative counterparts. More importantly, we found that these cells harbor HIV-1 DNA and replication-competent latent viruses at a significantly higher frequency. By using massive single-genome proviral sequencing from ART-suppressed individuals, we confirm that CD161+ CD4+ T cells contain remarkably more identical proviral sequences, indicating clonal expansion of the viral genome in these cells. Taking the results together, our study identifies infected CD161+ CD4+ T cells to be a critical force driving the clonal expansion of the HIV-1 latent reservoir, providing a novel mechanism for the long-term stability of HIV-1 latency. IMPORTANCE The latent reservoir continues to be the major obstacle to curing HIV-1 infection. The clonal expansion of latently infected cells adds another layer maintaining the long-term stability of the reservoir, but its mechanism remains unclear. Here, we report that CD161+ CD4+ T cells serve as an important compartment of the HIV-1 latent reservoir and contain a significant amount of clonally expanded proviruses. In our study, we describe a feasible strategy that may reduce the size of the latent reservoir to a certain extent by counterbalancing the repopulation and dissemination of latently infected cells.

scholarly journals Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of oxygen reactive species

2020 ◽  
Author(s):  
Anouk Lepez ◽  
Tiphène Pirnay ◽  
Sébastien Denanglaire ◽  
David Perez-Morga ◽  
Marjorie Vermeersch ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Effector Memory ◽  
T Cell Proliferation ◽  
Metabolic Enzyme ◽  
Ros Production

AbstractThe AMP-activated kinase (AMPK) is a major energy sensor metabolic enzyme that is activated early during T cell immune responses but its role in the generation of effector T cells is still controversial.Using both in vitro and in vivo models of T cell proliferation, we show herein that AMPK is dispensable for early TCR signaling and short-term proliferation but required for sustained long-term T cell proliferation and effector / memory T cell survival. In particular, AMPK promoted accumulation of effector / memory T cells in competitive homeostatic proliferation settings. Transplantation of AMPK-deficient hematopoïetic cells into allogeneic host recipients led to a reduced graft-versus-host disease, further bolstering a role for AMPK in the expansion and pathogenicity of effector T cells.Mechanistically, AMPK expression enhances the mitochondrial membrane potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Moreover, dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of T cell fitness.

HIV-Infected T Cells Induce Granzyme B-Secreting Regulatory B Cells in An Interleukin 21-Dependent Fashion,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3222-3222
Author(s):  
Christof Kaltenmeier ◽  
Karen Dahlke ◽  
Ali Gawanbacht ◽  
Thamara Beyer ◽  
Stefanie Hofmann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Acute Phase ◽  
Cd4 T Cells ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
T Cell Proliferation ◽  
Hiv 1

Abstract Abstract 3222 We and others have recently provided evidence that a series of lymphocyte subsets including, plasmacytoid dendritic cells, B cells and regulatory T cells are able to secrete the cytotoxic serine protease granzyme B (GrB) into the extracellular compartment, where it contributes to the suppression of T cell proliferation by a so far undefined GrB-dependent mechanism. For B cells, we found that viral antigens in the context of the acute phase cytokine interleukin (IL-) 21 can potently induce GrB. Here, we demonstrate that infection of CD4+ T cells with HIV-1 (NL4-3), but not mock infection, induces strong expression of IL-21 on both mRNA and protein levels in CD4+ T cells. Moreover, we found that HIV-infected CD4+ T cells are able to induce high levels of GrB in co-cultured B cells and that inhibition of IL-21 with specific antibodies abrogates T cell-mediated GrB induction in B cells. In support of these data, serum levels of both IL-21 and GrB are significantly higher in patients acutely infected with HIV as compared to healthy control subjects. Surprisingly, co-culture of CD4+ T cells with B cells during HIV-1 infection strongly suppressed both, proliferation of T cells as well as virus replication as indicated by significantly reduced p24 levels in culture supernatants. Notably, this effect was enhanced by external stimulation of B cells with IL-21, and was reduced by inhibition of GrB using specific GrB inhibitors. To further explore the underlying mechanisms of our findings, we performed confocal microscopy of T cell-B cell co-cultures and demonstrated that GrB-secreting B cells directly interact with CD4+ T cells, thereby transferring active GrB to them. Moreover, we found that GrB+ B cells decreased CD4+ T cell expression of the T cell receptor-zeta chain, a known GrB target, which is required for T cell proliferation, and known to be suppressed in HIV patients. In summary, we provide evidence that HIV induces the acute phase cytokine IL-21 in infected CD4+ T cells, thereby indirectly triggering the expression of GrB by B cells. GrB-secreting B cells may play a so far unappreciated role in decelerating the expansion of HIV, particularly in the early phase of acutely infected patients. Our study reveals a novel pathogenetic mechanism in HIV infection with potential relevance for the development of novel immunotherapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

PD-1/PD-L1 Blocking Enhances CD33/CD3-Bispecific BiTE® Antibody (AMG 330) Mediated Lysis of Primary AML Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3738-3738 ◽  
Author(s):  
Christina Krupka ◽  
Peter Kufer ◽  
Roman Kischel ◽  
Gerhard Zugmaier ◽  
Thomas Köhnke ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Primary Diagnosis ◽  
T Cell Proliferation ◽  
Employment Equity ◽  
Blocking Antibody ◽  
Equity Ownership

Abstract Antibody-based immunotherapy represents a promising strategy to target and eliminate chemoresistant leukemic cells in acute myeloid leukemia (AML). In our previous work, the potency of the CD33/CD3-bispecific BiTE® antibody AMG 330 to activate and redirect T-cells to AML cells was evaluated in a long-term culture system using unmanipulated peripheral blood (PB) or bone marrow (BM) samples from AML patients. We were able to show effective elimination of AML cells by AMG 330-activated and -expanded residual autologous T-cells (n=13, Krupka et. al, Blood 2014 123(3):356-65). The goal of the present study was to identify and manipulate factors that interfere with AMG 330-mediated lysis of primary AML cells. In our ex-vivo long-term culture system (n= 32 primary diagnosis, 3 relapse), we observed that successful elimination of primary AML cells was predominantly influenced by the initial effector:target (E:T) ratio. Reduced short-term lysis efficacy was observed for patient samples with low E:T ratios (median lysis: E:T ratio <1:10 23.5% vs >1:10 99.3%) after 4 days of culture. However, after 12 days of culture this effect was less prominent as effector T-cell numbers increased and lysis was observed even in cultures with very low initial E:T ratios (up to an E:T ratio of 1:80). Considering the ubiquitous expression pattern of CD33 within the myeloid compartment, the number of AMG 330 treatment days will be limited due to expected hematotoxicity. Therefore, AMG 330 efficacy might benefit by increasing the E:T ratio within a short time period. Programmed cell death-1 (PD-1) and its primary ligand PD-L1 are immune checkpoints that limit T-cell responses and may contribute to slower lysis kinetics during AMG 330 treatment. Therefore, we assessed PD-1 expression on T-cells and PD-L1 expression on primary AML cells. No constitutive expression of PD-1/PD-L1 on T-cells and corresponding AML cells was found at primary diagnosis (PD-1: n=23; PD-L1: n=193). Upon the addition of AMG 330 to our primary ex-vivo AML cultures, we observed a strong upregulation of PD-1 on activated T-cells, which correlated with the extent of T-cell proliferation (10/10). This was most prominent within the subpopulation of CD4+/CD45RA-/CCR7- effector memory T-cells. Furthermore, in response to AMG 330-mediated T-cell activation, we observed an upregulation of PD-L1 on primary AML cells (16/19). Data obtained from AML cell lines confirmed an upregulation of PD-L1 after co-cultivation with T-cells and AMG 330. This phenomenon was cytokine-mediated as the addition of IFNγ and TNFα also induced PD-L1 expression (n=6). Interestingly, we also observed a PD-L1 upregulation on T-cells upon activation with AMG 330, but to a much lower extent compared to primary AML cells (n=17; mean MFI ratio: T-cells: 4.7; AML cells: 12.1). Blockade of the PD-1/PD-L1 interaction through the addition of an inhibitory antibody induced an increase in T-cell proliferation in ex-vivocultures resulting in enhanced cytotoxicity against primary AML cells (lysis on day 18: with/without PD-1 blocking antibody: 75 vs 44%; fold change T-cell expansion: 6 vs 3). This was accompanied by a significant increase in IFNγ production (with/without PD-1 blocking antibody: 280 pg/ml vs 81 pg/ml). Complimentary experiments using primary AML cells and allogeneic T-cells at defined E:T ratios demonstrated that this effect is most prominent in co-cultures with a low percentage of T-cells within the primary sample (lysis on day 7 with/without PD-L1 blocking antibody: E:T ratio 1:1: 100% vs 94.5%; E:T ratio 1:5: 96.6% vs 82.7%; fold change T-cell expansion: E:T ratio 1:1: 3.1 vs 3.1; E:T ratio 1:5: 23.4 vs 9.8). Intriguingly, upon addition of lenalidomide to our primary AML cultures, we were also able to circumvent the immune inhibitory effect of the PD-1/PD-L1 interaction by a decrease in PD-L1 upregulation on primary AML cells. Our data show that AMG 330-mediated lysis of primary AML cells can be enhanced by inhibiting the PD-1/PD-L1 axis on T-cells and corresponding AML cells. The modulation of the PD-1/PD-L1 axis increased T-cell proliferation and accelerated attaining a beneficial E:T ratio. We hypothesize that PD-L1 upregulation on primary AML cells is a relevant immune escape mechanism employed by AML cells to escape cytokine-mediated immune responses. Prospective clinical trials will be needed to assess the relevance of our finding in AMG 330-treated AML patients. Disclosures Krupka: AMGEN Inc.: Research Funding. Kufer:AMGEN Inc.: Equity Ownership; AMGEN Research (Munich): Employment. Kischel:AMGEN Inc.: Equity Ownership; AMGEN Research (Munich): Employment. Zugmaier:AMGEN Research (Munich): Employment; AMGEN Inc.: Equity Ownership. Sinclair:AMGEN Inc.: Employment, Equity Ownership. Newhall:AMGEN Inc.: Employment, Equity Ownership. Frankel:AMGEN Inc.: Employment, Equity Ownership. Baeuerle:AMGEN Research (Munich): Employment; AMGEN Inc.: Equity Ownership. Riethmüller:AMGEN Inc.: Equity Ownership. Subklewe:AMGEN Inc.: Research Funding.

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