Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.

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Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4 + T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals

Cell Metabolism ◽

10.1016/j.cmet.2017.01.008 ◽

2017 ◽

Vol 25 (3) ◽

pp. 593-609 ◽

Cited By ~ 61

Author(s):

Claudio Mauro ◽

Joanne Smith ◽

Danilo Cucchi ◽

David Coe ◽

Hongmei Fu ◽

...

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Metabolic Stress ◽

T Cell Differentiation ◽

Cd4 T Cell ◽

Effector Memory

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Influence of cigarette-smoke extract conditioned medium on CD4+ T cell differentiation in vitro

Pneumologie ◽

10.1055/s-0033-1363104 ◽

2014 ◽

Vol 68 (02) ◽

Author(s):

N Baumgartl ◽

A Turowska ◽

H Garn

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Conditioned Medium ◽

Cigarette Smoke ◽

Cigarette Smoke Extract ◽

T Cell Differentiation ◽

Cd4 T Cell

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Faculty Opinions recommendation of Epigenetic silencing of CD8 genes by ThPOK-mediated deacetylation during CD4 T cell differentiation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717970758.793469184 ◽

2013 ◽

Author(s):

Remy Bosselut

Keyword(s):

Cell Differentiation ◽

T Cell ◽

T Cell Differentiation ◽

Epigenetic Silencing ◽

Cd4 T Cell

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Faculty Opinions recommendation of CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727407350.793529825 ◽

2017 ◽

Author(s):

Andrew Badley ◽

Nathan Cummins

Keyword(s):

T Cell ◽

Cd4 T Cell ◽

Hiv Reservoir

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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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