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Assessing the Innate Sensing of HIV-1 Infected CD4+ T Cells by Plasmacytoid Dendritic Cells Using an Ex vivo Co-culture System.
Published on: September 1, 2015
HIV-1 induces DCIR expression in CD4+ T cells
Alexandra A Lambert1, Michaël Imbeault, Caroline Gilbert
1Centre Hospitalier Universitaire de Québec-CHUL, Québec, Canada.
Insights
Human immunodeficiency virus-1 (HIV-1) increases C-type lectin receptor DCIR expression in CD4(+) T cells, potentially aiding virus spread. This discovery links HIV-1 infection to enhanced viral attachment, replication, and transfer.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- The C-type lectin receptor DCIR is primarily found on antigen-presenting cells and acts as an attachment factor for HIV-1 in dendritic cells.
- Recent findings identified DCIR in CD4(+) T cells from rheumatoid arthritis patients, challenging its restricted expression.
- HIV-1 infection and rheumatoid arthritis share characteristics like chronic inflammation and immune hyperactivation.
Purpose of the Study:
- To investigate if HIV-1 infection promotes DCIR expression in CD4(+) T cells.
- To elucidate the mechanisms underlying HIV-1-induced DCIR up-regulation.
- To determine the functional consequences of increased DCIR expression on HIV-1 pathogenesis.
Main Methods:
- Analysis of DCIR expression in CD4(+) T cells from HIV-1 infected patients (both treated and untreated) and in vitro infected cells.
- Investigation of soluble factors mediating DCIR up-regulation on uninfected cells.
- Infection studies using HIV-1 with deleted Vpr or Nef genes.
- Assessment of DCIR's role in apoptosis pathways.
- Evaluation of DCIR's impact on HIV-1 attachment, entry, replication, and transfer.
Main Results:
- HIV-1 infection demonstrably drives DCIR expression in primary human CD4(+) T cells, irrespective of patient treatment status or acute in vitro infection.
- Soluble factors released by HIV-1-infected cells are responsible for up-regulating DCIR on bystander uninfected cells.
- Viral genes Vpr and Nef are not implicated in the induction of DCIR expression following acute HIV-1 infection.
- DCIR expression is associated with both caspase-dependent and -independent intrinsic apoptotic pathways.
- Elevated surface DCIR on CD4(+) T cells correlates with enhanced HIV-1 attachment, entry, replication, and cell-to-cell transfer.
Conclusions:
- HIV-1 actively induces DCIR expression on CD4(+) T cells, a novel finding with significant implications for viral pathogenesis.
- This HIV-1-mediated DCIR up-regulation may contribute to the dissemination of the virus within the host.
- The study highlights a potential new mechanism by which HIV-1 exploits host cell machinery to promote its lifecycle and spread.
Abstract:
The C-type lectin receptor DCIR, which has been shown very recently to act as an attachment factor for HIV-1 in dendritic cells, is expressed predominantly on antigen-presenting cells. However, this concept was recently challenged by the discovery that DCIR can also be detected in CD4(+) T cells found in the synovial tissue from rheumatoid arthritis (RA) patients. Given that RA and HIV-1 infections share common features such as a chronic inflammatory condition and polyclonal immune hyperactivation status, we hypothesized that HIV-1 could promote DCIR expression in CD4(+) T cells. We report here that HIV-1 drives DCIR expression in human primary CD4(+) T cells isolated from patients (from both aviremic/treated and viremic/treatment naive persons) and cells acutely infected in vitro (seen in both virus-infected and uninfected cells). Soluble factors produced by virus-infected cells are responsible for the noticed DCIR up-regulation on uninfected cells. Infection studies with Vpr- or Nef-deleted viruses revealed that these two viral genes are not contributing to the mechanism of DCIR induction that is seen following acute infection of CD4(+) T cells with HIV-1. Moreover, we report that DCIR is linked to caspase-dependent (induced by a mitochondria-mediated generation of free radicals) and -independent intrinsic apoptotic pathways (involving the death effector AIF). Finally, we demonstrate that the higher surface expression of DCIR in CD4(+) T cells is accompanied by an enhancement of virus attachment/entry, replication and transfer. This study shows for the first time that HIV-1 induces DCIR membrane expression in CD4(+) T cells, a process that might promote virus dissemination throughout the infected organism.
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