Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV-infected HAART-suppressed individuals with poor CD4 T-cell recovery

Abstract Human immunodeficiency virus (HIV) infection is characterized by a progressive loss of memory CD4+ T cells in multiple tissues, especially at mucosal surfaces where most of these cells reside. Although antiretroviral therapy (ART) suppresses viral replication and promotes the recovery of peripheral CD4+ T cells, HIV-infected patients fail to fully reconstitute the CD4+ T-cell pool at mucosal sites. IL-15 has been shown to preferentially expand memory-phenotype T cells and promote their migration to nonlymphoid tissues. Here we examined IL-15 treatment in combination with highly active ART in chronically SIV-infected rhesus macaques and found that IL-15 delayed viral suppression and failed to enhance ART-induced total and antigen-specific CD4+ T-cell reconstitution at mucosal and lymphoid sites. IL-15 was able to induce the transient proliferation of SIV-specific, CMV-specific, and total memory CD8+ T cells, but not of SIV-specific or total CD4+ T cells. Moreover, upon treatment interruption, macaques receiving combined IL-15+ART lost CD4+ T cells faster than those receiving ART alone. These results suggest that the combination of IL-15 with highly active ART is not more efficient than ART alone in promoting CD4+ T-cell recovery in HIV-infected individuals and may accelerate CD4+ T-cell loss after treatment interruption.

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Kinetics of CD4+ T-cell recovery amongst HIV load suppressed patients on first-line antiretroviral therapy in Yaoundé, Cameroon

International Journal of Biological and Chemical Sciences ◽

10.4314/ijbcs.v15i3.3 ◽

2021 ◽

Vol 15 (3) ◽

pp. 881-888

Author(s):

Cedric Happi Mbakam ◽

Julius Mbekem Nwobegahay ◽

Cybelle Fodieu Mezajou ◽

Franklin Agueguia Azebaze ◽

Leopold Mbous Nguimbus ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Cd4 T Cells ◽

Standard Form ◽

University Teaching ◽

Cd4 T Cell ◽

Cell Recovery ◽

First Line ◽

Kinetics Of

HIV infected patients on Antiretroviral Therapy (ART) are exposed to various immunological disorders. Immune reconstitution is one of the most challenging problem linked to morbidity and mortality in HIV patients. This study aimed at evaluating the kinetics of CD4+ T-cell recovery amongst HIV load suppressed patients on first-line ART in Yaoundé, Cameroon. This was a retrospective cohort study performed at the care and treatment units of the Yaoundé University Teaching Hospital and Essos Hospital Center, with viral suppressed patients initiated on ART between March and July 2015. Data were collected using a standard form and analyzed using R.3.6.2 software. A p<0.05 was considered statistically significant for a 95%CI. Of the 499 viral suppressed participants, 32% (n=160) were male and 68% (n=339) female; 33% and 40% had severe and moderate immunodepression at baseline, respectively; 9% and 28% remain respectively on the same immunological state. CD4+ T-cell count increased by 73%, 49% and 29% for patients that started treatment, with CD4+ <150 cells/ml, 150<CD4+<350 cells/ml and 350<CD4+<500 cells/ml, respectively and 14%, 34% and 40% reached a target of 500 cells/ml or more after 4 years of treatment. Elder patients and males were likely to have CD4+ T-cells less than 350 Cells/ml. Approximately 35% of patient started treatment with CD4+ T-cells <350 Cells/ml. CD4+ T-cells increased significantly during 4 years of treatment but, just 29% in average achieved CD4+ ≥ 500 cells/ml. CD4 T-cells recovery represent and important challenge in the immunological monitoring of long-term HIV infected patients on ART.

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Slow disease progression and robust therapy-mediated CD4+ T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection

Blood ◽

10.1182/blood-2006-09-047308 ◽

2006 ◽

Vol 109 (7) ◽

pp. 2912-2920 ◽

Cited By ~ 48

Author(s):

Marie-Lise Dion ◽

Rebeka Bordi ◽

Joumana Zeidan ◽

Robert Asaad ◽

Mohammed-Rachid Boulassel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Disease Progression ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

Cell Recovery ◽

Cell Counts ◽

Patients Experience

AbstractIn chronic HIV infection, most untreated patients lose naive CD4+ and CD8+ T cells, whereas a minority preserve them despite persistent high viremia. Although antiretroviral therapy (ART)–mediated viral suppression generally results in a rise of naive and total CD4+ T cells, certain patients experience very little or no T-cell reconstitution. High peripheral T-cell activation has been linked to poor clinical outcomes, interfering with previous evaluations of thymic function in disease progression and therapy-mediated T-cell recovery. To circumvent this, we used the sj/βTREC ratio, a robust index of thymopoiesis that is independent of peripheral T-cell proliferation, to evaluate the thymic contribution to the preservation and restoration of naive CD4+ T cells. We show that the loss of naive and total CD4+ T cells is the result of or is exacerbated by a sustained thymic defect, whereas efficient thymopoiesis supports naive and total CD4+ T-cell maintenance in slow progressor patients. In ART-treated patients, CD4+ T-cell recovery was associated with the normalization of thymopoiesis, whereas the thymic defect persisted in aviremic patients who failed to recover CD4+ T-cell counts. Overall, we demonstrate that efficient thymopoiesis is key in the natural maintenance and in therapy-mediated recovery of naive and total CD4+ T cells.

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Platelets function as an acute viral reservoir during HIV-1 infection by harboring virus and T-cell complex formation

Blood Advances ◽

10.1182/bloodadvances.2020002420 ◽

2020 ◽

Vol 4 (18) ◽

pp. 4512-4521

Author(s):

Sydney R. Simpson ◽

Meera V. Singh ◽

Stephen Dewhurst ◽

Giovanni Schifitto ◽

Sanjay B. Maggirwar

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Complex Formation ◽

Platelet Activation ◽

Cd4 T Cells ◽

Cell Complex ◽

Cd4 T Cell ◽

Cell Recovery

Abstract Platelets were recently found to harbor infectious HIV virions in infected individuals who are on antiretroviral treatment with poor CD4+ T-cell recovery. In this study, we screened platelets from recently infected individuals, before and after antiretroviral therapy, for the presence of virus and examined platelet activation, as well as CD4+ T-cell recovery. This was followed by in vitro studies assessing platelet–CD4+ T-cell complex formation as a contributing factor to viral transmission. HIV+ platelets were detected in 10 of 10 acutely infected individuals with no prior history of antiretroviral therapy. The percentage of HIV+ platelets dropped significantly after 3 months of antiretroviral therapy in all of the study participants. These individuals also demonstrated significant recovery of CD4+ T cells. Interestingly, the percentage of HIV+ platelets correlated positively with viral load but not with CD4+ T-cell count. Furthermore, we found that platelet activation with soluble CD40L or thrombin receptor activator peptide 6 (TRAP6) increased platelet-virus interactions in vitro. TRAP6-mediated interactions were reduced by platelet antagonists, aspirin, and R406. We demonstrated that platelets transmit the virus to CD4+ T cells, and this transinfection was abolished by inhibiting platelet–T-cell complex formation via exposure to an anti-CD62P antibody. Additionally, treatment with TRAP6 significantly increased the transinfection, which was also inhibited by aspirin and R206. These results reveal that platelets have the potential to promote HIV viral spread during the acute stage of infection, by harboring infectious virus transmitting infection to susceptible CD4+ T cells through complex formation.

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Responsiveness to IL-7 but not to IFN-α is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery

AIDS ◽

10.1097/qad.0000000000001161 ◽

2016 ◽

Vol 30 (13) ◽

pp. 2033-2042 ◽

Cited By ~ 8

Author(s):

Thao P. Nguyen ◽

Supriya Shukla ◽

Robert Asaad ◽

Michael L. Freeman ◽

Michael M. Lederman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Recovery

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HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

Frontiers in Immunology ◽

10.3389/fimmu.2018.01673 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Isaac Rosado-Sánchez ◽

Inés Herrero-Fernández ◽

Miguel Genebat ◽

Jorge Del Romero ◽

Melchor Riera ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Effective Therapy ◽

Cd4 T Cell ◽

Cell Recovery ◽

Prior Therapy ◽

Therapy Initiation

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Increased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART

PLoS Pathogens ◽

10.1371/journal.ppat.1009825 ◽

2021 ◽

Vol 17 (8) ◽

pp. e1009825

Author(s):

Maria Pino ◽

Susan Pereira Ribeiro ◽

Amélie Pagliuzza ◽

Khader Ghneim ◽

Anum Khan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Cell Recovery ◽

Cd4 Cell Count ◽

Hiv Dna ◽

Art Initiation ◽

Cd4 Cell

Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART.

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Addition of maraviroc to antiretroviral therapy decreased interferon-γ mRNA in the CD4+ T cells of patients with suboptimal CD4+ T-cell recovery

Journal of Infection and Chemotherapy ◽

10.1016/j.jiac.2016.09.003 ◽

2017 ◽

Vol 23 (1) ◽

pp. 29-34 ◽

Cited By ~ 5

Author(s):

Rumi Minami ◽

Soichiro Takahama ◽

Yu Kaku ◽

Masahiro Yamamoto

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Cd4 T Cells ◽

Interferon Γ ◽

Cd4 T Cell ◽

Cell Recovery

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Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

Immunity & Ageing ◽

10.1186/s12979-021-00217-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Stephanie M. Dillon ◽

Tezha A. Thompson ◽

Allison J. Christians ◽

Martin D. McCarter ◽

Cara C. Wilson

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Older Persons ◽

Age Groups ◽

T Cell Immunity ◽

Cd4 T Cell ◽

Cell Immunity ◽

Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

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The Impact of Exercise Serum on Selected Parameters of CD4+ T Cell Metabolism

Immuno ◽

10.3390/immuno1030008 ◽

2021 ◽

Vol 1 (3) ◽

pp. 119-131

Author(s):

Jana Palmowski ◽

Kristina Gebhardt ◽

Thomas Reichel ◽

Torsten Frech ◽

Robert Ringseis ◽

...

Keyword(s):

T Cells ◽

Oxygen Consumption ◽

T Cell ◽

Real Time ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Autologous Serum ◽

Cell Phenotype ◽

The Impact

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

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