Susceptibility to opportunistic infections in HIV-infected patients with increased CD4 T-cell counts on antiretroviral therapy may be predicted by markers of dysfunctional effector memory CD4 T cells and B cells

Abstract Background Ethiopia initiated antiretroviral therapy early in 2005. Managing and detecting antiretroviral treatment response is important to monitor the effectiveness of medication and possible drug switching for low immune reconstitution. There is less recovery of CD4+ T cells among human immunodeficiency virus patients infected with tuberculosis. Hence, we aimed to assess the effect of tuberculosis and other determinant factors of immunological response among human immunodeficiency virus patients on highly active antiretroviral therapy. A retrospective follow up study was conducted from October to July 2019. A total of 393 participants were enrolled. An interviewer based questionnaire was used for data collection. Patient charts were used to extract clinical data and follow up results of the CD4+ T cell. Current CD4+ T cell counts of patients were performed. STATA 13 software was used to analyze the data. A p-value ≤0.05 was considered a statistically significant association. Results The mean age of study participants was 39.2 years (SD: + 12.2 years) with 8.32 mean years of follow up. The overall prevalence of immune reconstitution failure was 24.7% (97/393). Highest failure rate occurred within the first year of follow up time, 15.7 per 100 Person-year. Failure of CD4+ T cells reconstitution was higher among tuberculosis coinfected patients (48.8%) than mono-infected patients (13.7%). Living in an urban residence, baseline CD4+ T cell count ≤250 cells/mm3, poor treatment adherence and tuberculosis infection were significantly associated with the immunological failure. Conclusions There was a high rate of CD4+ T cells reconstitution failure among our study participants. Tuberculosis infection increased the rate of failure. Factors like low CD4+ T cell baseline count, poor adherence and urban residence were associated with the immunological failure. There should be strict monitoring of CD4+ T cell counts among individuals with tuberculosis coinfection.

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Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20112631 ◽

2012 ◽

Vol 209 (13) ◽

pp. 2383-2394 ◽

Cited By ~ 20

Author(s):

Atsushi Nishida ◽

Kiyotaka Nagahama ◽

Hirotsugu Imaeda ◽

Atsuhiro Ogawa ◽

Cindy W. Lau ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Expansion ◽

Intestinal Inflammation ◽

Cd4 T Cell ◽

Effector Memory ◽

Glycan Structure ◽

T Cell Expansion ◽

Memory Cd4 T Cells

Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1–expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell–mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

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Antigen Presenting B Cells Facilitate CD4 T Cell Cooperation Resulting in Enhanced Generation of Effector and Memory CD4 T Cells

PLoS ONE ◽

10.1371/journal.pone.0077346 ◽

2013 ◽

Vol 8 (10) ◽

pp. e77346 ◽

Cited By ~ 13

Author(s):

David R. Kroeger ◽

Christopher D. Rudulier ◽

Peter A. Bretscher

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Antigen Presenting ◽

Memory Cd4 T Cells ◽

Cell Cooperation

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Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

Journal of Fungi ◽

10.3390/jof5030063 ◽

2019 ◽

Vol 5 (3) ◽

pp. 63

Author(s):

Alice Bayiyana ◽

Samuel Okurut ◽

Rose Nabatanzi ◽

Godfrey Zziwa ◽

David R. Boulware ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Surface ◽

Cd8 T Cells ◽

Cryptococcal Meningitis ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Effector Memory ◽

Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

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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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Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function

Clinical Immunology ◽

10.1016/j.clim.2006.04.570 ◽

2006 ◽

Vol 120 (2) ◽

pp. 163-170 ◽

Cited By ~ 42

Author(s):

Sonia Fernandez ◽

Patricia Price ◽

Elizabeth J. McKinnon ◽

Richard C. Nolan ◽

Martyn A. French

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Cd4 T Cell ◽

Effector Memory ◽

Hiv Patients ◽

Memory T Cell ◽

Cell Counts

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PIMATM point-of-care testing for CD4 counts in predicting antiretroviral initiation in HIV-infected individuals in KwaZulu-Natal, Durban, South Africa

Southern African Journal of HIV Medicine ◽

10.4102/sajhivmed.v17i1.444 ◽

2016 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Mandisa Skhosana ◽

Shabashini Reddy ◽

Tarylee Reddy ◽

Siphelele Ntoyanto ◽

Elizabeth Spooner ◽

...

Keyword(s):

South Africa ◽

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Cell Count ◽

Point Of Care ◽

Cd4 T Cell ◽

Cell Counts ◽

Kwazulu Natal ◽

Cd4 T Cell Count

Introduction: Limited information is available on the usefulness of the PIMATM analyser in predicting antiretroviral treatment eligibility and outcome in a primary healthcare clinic setting in disadvantaged communities in KwaZulu-Natal, South Africa.Materials and methods: The study was conducted under the eThekwini Health Unit, Durban, KwaZulu-Natal. Comparison of the enumeration of CD4+ T-cells in 268 patients using the PIMATM analyser and the predicate National Health Laboratory Services (NHLS) was undertaken during January to July 2013. Bland-Altman analysis to calculate bias and limits of agreement, precision and levels of clinical misclassification at various CD4+ T-cell count thresholds was performed.Results: There was high precision of the PIMATM control bead cartridges with low and normal CD4+ T-cell counts using three different PIMATM analysers (%CV < 5). Under World Health Organization (WHO) guidelines (≤ 500 cells/mm3), the sensitivity of the PIMATM analyser was 94%, specificity 78% and positive predictive value (PPV) 95%. There were 24 (9%) misclassifications, of which 13 were false-negative in whom the mean bias was 149 CD4+ T-cells/mm3. Most (87%) patients returned for their CD4 test result but only 67% (110/164) of those eligible (≤ 350 cells/mm3) were initiated on antiretroviral therapy (ART) with a time to treatment of 49 days (interquartile range [IQR], 42–64 days).Conclusion: There was adequate agreement between PIMATM analyser and predicate NHLS CD4+ T-cell count enumeration (≤ 500 cells/mm3) in adult HIV-positive individuals. The high PPV, sensitivity and acceptable specificity of the PIMATM analyser technology lend it as a reliable tool in predicting eligibility and rapid linkage to care in ART programmes.Keywords: HIV; Point of Care; PIMATM CD4+ T cell counts; antiretroviral therapy; prediction/eligibility; South Africa

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The ARTμS: a novel microfluidic CD4+ T-cell enumeration system for monitoring antiretroviral therapy in HIV patients

Lab on a Chip ◽

10.1039/c5lc01153a ◽

2016 ◽

Vol 16 (3) ◽

pp. 506-514 ◽

Cited By ~ 9

Author(s):

Qian Liu ◽

Alexis Chernish ◽

Jacquelyn A. DuVall ◽

Yiwen Ouyang ◽

Jingyi Li ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Microfluidic Device ◽

Dna Content ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Hiv Patients ◽

Cell Enumeration

An integrated microfluidic device that enumerates CD4+ T-cells based on DNA content.

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HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity

Journal of Experimental Medicine ◽

10.1084/jem.20031598 ◽

2003 ◽

Vol 198 (12) ◽

pp. 1909-1922 ◽

Cited By ~ 339

Author(s):

Souheil-Antoine Younes ◽

Bader Yassine-Diab ◽

Alain R. Dumont ◽

Mohamed-Rachid Boulassel ◽

Zvi Grossman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Memory Cells ◽

Cell Responses ◽

Specific Memory ◽

Ifn Γ ◽

Memory Cd4 T Cells

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-γ–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-γ only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-γ only–producing cells that lack self-renewal capacity.

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