Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6 ⁺ CD4 ⁺ T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection

Abstract

In this study, we investigated the effect of Toll-like receptor 2 (TLR2) ligation on the permissiveness of activated CD4 ϩ T cells to HIV-1 infection by focusing our experiments on the relative susceptibility of cell subsets based on their expression of CCR6. Purified primary human CD4 ϩ T cells were first subjected to a CD3/CD28 costimulation before treatment with the TLR2 agonist Pam3CSK4. Finally, cells were inoculated with R5-tropic HIV-1 particles that permit us to study the effect of TLR2 triggering on virus production at both population and single-cell levels. We report here that HIV-1 replication is augmented in CD3/CD28-costimulated CCR6 ϩ CD4 ϩ T cells upon engagement of the cell surface TLR2. Additional studies indicate that a higher virus entry and polymerization of the cortical actin are seen in this cell subset following TLR2 stimulation. A TLR2-mediated increase in the level of phosphorylated NF-B p65 subunit was also detected in CD3/CD28-costimulated CCR6 ϩ CD4 ϩ T cells. We propose that, upon antigenic presentation, an engagement of TLR2 acts specifically on CCR6 ϩ CD4 ϩ T cells by promoting virus entry in an intracellular milieu more favorable for productive HIV-1 infection.IMPORTANCE Following primary infection, HIV-1 induces an immunological and structural disruption of the gut mucosa, leading to bacterial translocation and release of microbial components in the bloodstream. These pathogen-derived constituents include several agonists of Toll-like receptors that may affect gut-homing CD4 ϩ T cells, such as those expressing the chemokine receptor CCR6, which are highly permissive to HIV-1 infection. We demonstrate that TLR2 ligation in CD3/ CD28-costimulated CCR6 ϩ CD4 ϩ T cells leads to enhanced virus production. Our results highlight the potential impact of bacterial translocation on the overall permissiveness of CCR6 ϩ CD4 ϩ T cells to productive HIV-1 infection. KEYWORDS CD4 ϩ T cells, NF-B, human immunodeficiency virus

A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV

“…Further, we find that TLR2 mediates enhanced infection of THP-1 cells by HIV-1 regardless of viral entry pathway used, as it impacted infection through both the HIV envelope and the VSV-G glycoprotein ( Figure 5E ). Recent work in CD4 +T cells has similarly demonstrated enhanced infection and/or viral production in T cells on stimulation of TLR2 ( Bolduc et al, 2017 ; Ding and Chang, 2012 ; Ding et al, 2010 ; Equils et al, 2003 ; Henrick et al, 2015 ). Of note, MYD88, a downstream effector for TLR2 activation of transcription, is also a strong hit in our dependency factor screening ( Figure 5A ) suggesting that it is the downstream signaling functions of TLR2 that enhance infection.…”

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“…The role of ATRA in regulating tolerance and immunity via the modulation of regulatory and effector functions of CD4 + T cells, respectively, is well established (41) Considering the strategic location of Th17 cells at portal sites of HIV/SIV entry (6,24,27,28,63), as well as their important role in maintaining mucosal immunity homeostasis in the context of a complex microbiota (6,64,65), our results point to the potential beneficial use of mTOR inhibitors in preventing HIV infection/ persistence in gut-homing Th17 cells.…”

Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage

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