HIV-1 infection of CD4 T cells impairs antigen-specific B cell function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA656774 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND: Combination antiretroviral therapy (cART) is able to control HIV-1 viral replication, however long-lived latent infection in resting memory CD4+ T-cells persist. The mechanisms for establishment and maintenance of latent infection in resting memory CD4+ T-cells remain unclear. Previously we have shown that HIV-1 infection of resting CD4+ T-cells co-cultured with CD11c+ myeloid dendritic cells (mDC) produced a population of non-proliferating T-cells with latent infection. Here we asked whether different antigen presenting cells (APC), including subpopulations of DC and monocytes, were able to induce post-integration latent infection in resting CD4+ T-cells, and examined potential cell interactions that may be involved using RNA-seq. RESULTS: mDC (CD1c+), SLAN+ DC and CD14+ monocytes were most efficient in stimulating proliferation of CD4+ T-cells during syngeneic culture and in generating post-integration latent infection in non-proliferating CD4+ T-cells following HIV-1 infection of APC-T-cell co-cultures. In comparison, plasmacytoid DC (pDC) and B-cells did not induce latent infection in APC-T-cell co-cultures. We compared the RNA expression profiles of APC subpopulations that could and could not induce latency in non-proliferating CD4+ T-cells. Gene expression analysis, comparing the mDC, SLAN+ DC and CD14+ monocyte subpopulations to pDC identified 53 upregulated genes that encode proteins expressed on the plasma membrane that could signal to CD4+ T-cells via cell-cell interactions (32 genes), immune checkpoints (IC) (5 genes), T-cell activation (9 genes), regulation of apoptosis (5 genes), antigen presentation (1 gene) and through unknown ligands (1 gene). CONCLUSIONS: APC subpopulations from the myeloid lineage, specifically mDC subpopulations and CD14+ monocytes, were able to efficiently induce post-integration HIV-1 latency in non-proliferating CD4+ T-cells in vitro. Inhibition of key pathways involved in mDC-T-cell interactions and HIV-1 latency may provide novel targets to eliminate HIV latency. mRNA profiles of sorted, pure antigen presenting cells including, CD1c+ myleoid dendirtic cells (mDC), SLAN+ mDC, CD14+ monocytes and plasmacytoid DC (pDC), were generated using next generation sequencing in triplicate, using Illumina Illumina Hiseq 2000.
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Project description:The clonal expansion of HIV-1-infected CD4+ T cells is a major barrier to cure. Using single-cell ECCITE-seq, we examined the transcriptional landscape, upstream immune regulators, HIV-1 RNA expression, and T cell clonal expansion dynamics of 215,458 CD4+ T cells (267 HIV-1 RNA+ cells and 68 expanded HIV-1 RNA+ T cell clones) from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. We found that despite antiretroviral therapy, antigen and TNF responses persisted and shaped T cell clonal expansion. HIV-1 resided in Th1 polarized, antigen-responding T cells expressing Bcl-2 family anti-apoptotic genes. HIV-1 RNA+ T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB+ cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4+ T cells and drivers of clonal expansion provides a new direction for HIV-1 eradication.
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Project description:Wodarz2007 - HIV/CD4 T-cell interaction
A deterministic model illustrating how
CD4 T-cells can influence HIV infection.
This model is described in the article:
Infection dynamics in
HIV-specific CD4 T cells: does a CD4 T cell boost benefit the
host or the virus?
Wodarz D, Hamer DH.
Math Biosci 2007 Sep; 209(1):
14-29
Abstract:
Recent experimental data have shown that HIV-specific CD4 T
cells provide a very important target for HIV replication. We
use mathematical models to explore the effect of specific CD4 T
cell infection on the dynamics of virus spread and immune
responses. Infected CD4 T cells can provide antigen for their
own stimulation. We show that such autocatalytic cell division
can significantly enhance virus spread, and can also provide an
additional reservoir for virus persistence during anti-viral
drug therapy. In addition, the initial number of HIV-specific
CD4 T cells is an important determinant of acute infection
dynamics. A high initial number of HIV-specific CD4 T cells can
lead to a sudden and fast drop of the population of
HIV-specific CD4 T cells which results quickly in their
extinction. On the other hand, a low initial number of
HIV-specific CD4 T cells can lead to a prolonged persistence of
HIV-specific CD4 T cell help at higher levels. The model
suggests that boosting the population of HIV-specific CD4 T
cells can increase the amount of virus-induced immune
impairment, lead to less efficient anti-viral effector
responses, and thus speed up disease progression, especially if
effector responses such as CTL have not been sufficiently
boosted at the same time.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000663.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000663 | BioModels
Project description:HIV-1 spreads between CD4 T cells most efficiently through virus-induced cell-cell contacts. To test whether this process potentiates viral spread by activating signaling pathways we developed an approach to analyze the phosphoproteome in infected and uninfected mixed population T cells using differential metabolic labeling and mass spectrometry. We discovered HIV-1 induced activation of signaling networks during viral spread encompassing over 200 cellular proteins. Strikingly, pathways downstream of T cell receptor were the most significantly activated, despite the absence of canonical antigen dependent stimulation. The importance of this pathway was demonstrated by depletion of proteins and we show that HIV-1 Env mediated cell-cell contact, T cell receptor and the Src kinase Lck were essential for signaling dependent enhancement of viral dissemination. This study demonstrates that manipulation of signaling at immune cell contacts by HIV-1 is essential for promoting virus replication and defines a new paradigm for antigen independent T cell signaling.
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