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

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.

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TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis

Journal of Experimental Medicine ◽

10.1084/jem.20090153 ◽

2009 ◽

Vol 206 (10) ◽

pp. 2111-2119 ◽

Cited By ~ 61

Author(s):

Ning Lu ◽

Yi-Hong Wang ◽

Yui-Hsi Wang ◽

Kazuhiko Arima ◽

Shino Hanabuchi ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Th2 Cells ◽

T Cell Proliferation ◽

T Cell Homeostasis ◽

Cell Homeostasis ◽

Th2 Differentiation

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis.

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Gag-Specific CD4 T Cell Proliferation, Plasmacytoid Dendritic Cells, and Ethnicity in Perinatally HIV-1-Infected Youths: The ANRS-EP38-IMMIP Study

AIDS Research and Human Retroviruses ◽

10.1089/aid.2016.0177 ◽

2017 ◽

Vol 33 (1) ◽

pp. 21-28

Author(s):

Daniel Scott-Algara ◽

Josiane Warszawski ◽

Jérôme Le Chenadec ◽

Céline Didier ◽

Thomas Montange ◽

...

Keyword(s):

Cell Proliferation ◽

Dendritic Cells ◽

T Cell ◽

Plasmacytoid Dendritic Cells ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Hiv 1

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The C-class chemokine, lymphotactin, impairs the induction of Th1-type lymphokines in human CD4+ T cells

Blood ◽

10.1182/blood.v96.2.420 ◽

2000 ◽

Vol 96 (2) ◽

pp. 420-428 ◽

Cited By ~ 25

Author(s):

Chantal Cerdan ◽

Edgar Serfling ◽

Daniel Olive

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Jurkat Cells ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Human T Cell

Abstract Chemokines are involved in the regulation of leukocyte migration and for some of them, T-cell costimulation. To date, the only direct property of lymphotactin (Lptn), the unique member of the C class of chemokines, consists of T-cell chemoattraction. This report describes a novel function for Lptn in human T-lymphocyte biology, by demonstrating the direct ability of Lptn to both inhibit and costimulate CD4+ and CD8+ T-cell activation, respectively. Lptn but not RANTES inhibited CD4+ T-cell proliferation, through a decreased production of Th1 (interleukin [IL]-2, interferon [IFN]-γ) but not Th2 (IL-4, IL-13) lymphokines, and decreased IL-2R expression. Transfections in Jurkat cells showed a Lptn-mediated transcriptional down-regulation of gene-promoter activities specific for Th1-type lymphokines, as well as of nuclear factor of activated T cells (NF-AT) but not AP-1 or NF-ΚB enhancer activities. This suppressive action of Lptn could be compensated by overexpression of NF-ATc but not NF-ATp. CD4+ T-cell proliferation was completely restored by exogenous IL-2 or reversed by pertussis toxin, wortmannin, and genistein, suggesting the involvement of multiple partners in Lptn signaling. In contrast to CD4+ cells, Lptn exerted a potent costimulatory activity on CD8+ T-cell proliferation and IL-2 secretion. These data provide important insights into the role of Lptn in differential regulation of normal human T-cell activation and its possible implication in immune response disorders.

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The Effects of Stimulation with PMA/Ionomycin on CD4+ T cell Proliferation and Surface CD4 Molecule Modulation of Patients with LRBA Deficiency and CVID with the Unsolved Genetic Defect

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530321666211209162834 ◽

2021 ◽

Vol 21 ◽

Author(s):

Fereshte Salami ◽

Sahar Shariati ◽

Seyed Erfan Rasouli ◽

Samaneh Delavari ◽

Marziyeh Tavakol ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Healthy Individuals ◽

Cell Frequency ◽

Before And After ◽

Lrba Deficiency

Background: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiencies. LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency characterized by a CVID-like phenotype. Affected patients by LRBA and CVID present a wide range of clinical manifestations, including hypogammaglobulinemia, recurrent infections, autoimmunity, as well as T cell abnormality. Methods: The study population comprised of patients with CVID (n=10), LRBA deficiency (n=11), and healthy controls (n=12). CD4+ T cell frequency and CD4 MFI (mean fluorescence intensity) were evaluated using flow cytometry before and after stimulation with PMA/ION. Results: The frequencies of CD4+ T cells were significantly lower in patients with LRBA deficiency than in HCs before and after treatment. In the unstimulated state, the CD4+ T cells frequency in CVID patients was significantly lower than in HCs. There were no statistically significant differences between patients and healthy individuals in CD4+ T cell proliferation. Compared to HCs, LRBA and CVID patients showed a lower CD4 MFI in unstimulated conditions. Furthermore, CD4 MFI decreased in both patients and the control group following activation. Conclusion : Despite the reported decrease in CD4+ T cell frequency in patients with CVID and LRBA deficiency, our findings demonstrated that their CD4+ T cells have a normal proliferative response to stimuli similar to healthy individuals.

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Bone marrow–based homeostatic proliferation of mature T cells in nonhuman primates: implications for AIDS pathogenesis

Blood ◽

10.1182/blood-2008-06-159442 ◽

2009 ◽

Vol 113 (3) ◽

pp. 612-621 ◽

Cited By ~ 20

Author(s):

Mirko Paiardini ◽

Barbara Cervasi ◽

Jessica C. Engram ◽

Shari N. Gordon ◽

Nichole R. Klatt ◽

...

Keyword(s):

Bone Marrow ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Homeostatic Proliferation ◽

T Cell Homeostasis ◽

Cell Homeostasis

AbstractBone marrow (BM) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory CD8+ T cells. Here we expanded on our previous observation that BM is a preferential site for T-cell proliferation in simian immunodeficiency virus (SIV)–infected sooty mangabeys (SMs) that do not progress to AIDS despite high viremia. We found high levels of mature T-cell proliferation, involving both naive and memory cells, in healthy SMs and rhesus macaques (RMs). In addition, we observed in both species that lineage-specific, BM-based T-cell proliferation follows antibody-mediated in vivo CD4+ or CD8+ T-cell depletion, thus indicating a role for the BM in maintaining T-cell homeostasis under depleting circumstances. We also observed that, in SIV-infected SMs, but not RMs, the level of proliferation of BM-based CD4+ T cells is higher than that of circulating CD4+ T cells. Interestingly, limited BM-based CD4+ T-cell proliferation was found in SIV-infected SMs with low CD4+ T-cell counts, suggesting a regenerative failure in these animals. Collectively, these results indicate that BM is involved in maintaining T-cell homeostasis in primates and suggest a role for BM-based CD4+ T-cell proliferation in determining the benign nature of natural SIV infection of SMs.

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

Clinical Immunology ◽

10.1006/clim.2001.5102 ◽

2001 ◽

Vol 101 (2) ◽

pp. 180-191 ◽

Cited By ~ 19

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

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Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4+ T cell proliferation

Virology ◽

10.1016/j.virol.2013.02.018 ◽

2013 ◽

Vol 440 (2) ◽

pp. 150-159 ◽

Cited By ~ 1

Author(s):

Wan Liu ◽

Yan Qin ◽

Lei Bai ◽

Ke Lan ◽

Jian-Hua Wang

Keyword(s):

Cell Proliferation ◽

Dendritic Cells ◽

T Cell ◽

Kaposi's Sarcoma ◽

Kaposi’S Sarcoma ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Trans Infection ◽

Kaposi’S Sarcoma Associated Herpesvirus ◽

Hiv 1

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High Beta-Chemokine Expression Levels in Lymphoid Tissues of Simian/Human Immunodeficiency Virus 89.6-Vaccinated Rhesus Macaques Are Associated with Uncontrolled Replication of Simian Immunodeficiency Virus Challenge Inoculum

Journal of Virology ◽

10.1128/jvi.78.12.6399-6408.2004 ◽

2004 ◽

Vol 78 (12) ◽

pp. 6399-6408 ◽

Cited By ~ 10

Author(s):

Lisa LaFranco-Scheuch ◽

Kristina Abel ◽

Norbert Makori ◽

Kristina Rothaeusler ◽

Christopher J. Miller

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Viral Replication ◽

Simian Immunodeficiency Virus ◽

T Cell Proliferation ◽

Expression Levels ◽

Immunodeficiency Virus

ABSTRACT Viral suppression by noncytolytic CD8+ T cells, in addition to that by classic antiviral CD8+ cytotoxic T lymphocytes, has been described for human immunodeficiency virus and simian immunodeficiency virus (SIV) infections. However, the role of soluble effector molecules, especially beta-chemokines, in antiviral immunity is still controversial. In an attenuated vaccine model, approximately 60% of animals immunized with simian/human immunodeficiency virus (SHIV) 89.6 and then challenged intravaginally with SIVmac239 controlled viral replication (viral RNA level in plasma, <104 copies/ml) and were considered protected (K. Abel, L. Compton, T. Rourke, D. Montefiori, D. Lu, K. Rothaeusler, L. Fritts, K. Bost, and C. J. Miller, J. Virol. 77:3099-3118, 2003). To determine the in vivo importance of beta-chemokine secretion and CD8+-T-cell proliferation in the control of viral replication in this vaccine model, we examined the relationship between viral RNA levels in the axillary and genital lymph nodes of vaccinated, protected (n = 20) and vaccinated, unprotected (n = 11) monkeys by measuring beta-chemokine mRNA levels and protein expression, the frequency of CD8+ T cells expressing beta-chemokines, and the extent of CD8+-T-cell proliferation. Tissues from uninfected (n = 3) and unvaccinated, SIVmac239-infected (n = 9) monkeys served as controls. Axillary and genital lymph nodes from unvaccinated and vaccinated, unprotected monkeys had significantly higher beta-chemokine mRNA expression levels and increased numbers of beta-chemokine-positive cells than did vaccinated, protected animals. Furthermore, the lymph nodes of vaccinated, unprotected monkeys had significantly higher numbers of beta-chemokine+ CD8+ T cells than did vaccinated, protected monkeys. Lymph nodes from vaccinated, unprotected animals also had significantly more CD8+-T-cell proliferation and marked lymph node hyperplasia than the lymph nodes of vaccinated, protected monkeys. Thus, higher levels of virus replication were associated with increased beta-chemokine secretion and there is no evidence that beta-chemokines contributed to the SHIV89.6-mediated control of viral replication after intravaginal challenge with SIVmac239.

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Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2010.0972 ◽

2010 ◽

Vol 277 (1701) ◽

pp. 3773-3781 ◽

Cited By ~ 14

Author(s):

Ming Liang Chan ◽

Janka Petravic ◽

Alexandra M. Ortiz ◽

Jessica Engram ◽

Mirko Paiardini ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Number ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Proliferating Cells ◽

Immunodeficiency Virus ◽

Sooty Mangabeys

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

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