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TLR2 and TLR4 triggering exerts contrasting effects with regard to HIV-1 infection of human dendritic cells and subsequent virus transfer to CD4+ T cells.

Thibault S, Fromentin R, Tardif MR, Tremblay MJ - Retrovirology (2009)

Bottom Line: Recognition of microbial products through Toll-like receptors (TLRs) initiates inflammatory responses orchestrated by innate immune cells such as dendritic cells (DCs).No noticeable and consistent effect was observed following engagement of TLR5, 7 and 9.Additional studies indicated that both HIV-1 infection of DCs and DC-mediated virus transmission to CD4+ T cells were reduced upon TLR4 triggering due to secretion of type-I interferons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculté de Médecine, Université Laval, Québec, Canada. sandra.thibault@crchul.ulaval.ca

ABSTRACT

Background: Recognition of microbial products through Toll-like receptors (TLRs) initiates inflammatory responses orchestrated by innate immune cells such as dendritic cells (DCs). As these cells are patrolling mucosal surfaces, a portal of entry for various pathogens including human immunodeficiency virus type-1 (HIV-1), we investigated the impact of TLR stimulation on productive HIV-1 infection of DCs and viral spreading to CD4+ T cells.

Results: We report here that engagement of TLR2 on DCs increases HIV-1 transmission toward CD4+ T cells by primarily affecting de novo virus production by DCs. No noticeable and consistent effect was observed following engagement of TLR5, 7 and 9. Additional studies indicated that both HIV-1 infection of DCs and DC-mediated virus transmission to CD4+ T cells were reduced upon TLR4 triggering due to secretion of type-I interferons.

Conclusion: It can thus be proposed that exposure of DCs to TLR2-binding bacterial constituents derived, for example, from pathogens causing sexually transmissible infections, might influence the process of DC-mediated viral dissemination, a phenomenon that might contribute to a more rapid disease progression.

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TLR4-mediated decrease in de novo virus production involves type-I IFNs. A) IM-MDDCs were either left untreated (mock) or stimulated for 6 hours with the listed TLR ligands. Cell-free supernatants were harvested and the levels of IFNα/β were quantified through the use of HEK-Blue™ IFNα/β cells. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor. B) IM-MDDCs were either left untreated (mock) or stimulated for 2 hours with the TLR4 ligand LPS. Cells were then washed twice, pulsed with NL4-3/Balenv and cultured in absence or presence of B18R (0.1 μg/ml). Supernatants were harvested at 72 hours post-infection and the viral content was evaluated by a p24 test. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor and are representative of 4 different donors.
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Figure 8: TLR4-mediated decrease in de novo virus production involves type-I IFNs. A) IM-MDDCs were either left untreated (mock) or stimulated for 6 hours with the listed TLR ligands. Cell-free supernatants were harvested and the levels of IFNα/β were quantified through the use of HEK-Blue™ IFNα/β cells. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor. B) IM-MDDCs were either left untreated (mock) or stimulated for 2 hours with the TLR4 ligand LPS. Cells were then washed twice, pulsed with NL4-3/Balenv and cultured in absence or presence of B18R (0.1 μg/ml). Supernatants were harvested at 72 hours post-infection and the viral content was evaluated by a p24 test. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor and are representative of 4 different donors.

Mentions: Knowing that TLR4 stimulation can lead to secretion of type-I IFNs (i.e. IFNα and IFNβ), we next wanted to see whether the observed TLR4-dependent diminution in virus replication was attributable to these antiviral agents. To demonstrate the participation of type-I IFNs in the LPS-dependent modulatory effect on virus production in IM-MDDCs, we performed experiments with HEK-Blue™ IFNα/β indicator cells. Results depicted in Fig. 8A indicate that the TLR4 ligand LPS acted as a strong inducer of IFNα/β in IM-MDDCs while TLR2, 5, 7 and 9 triggering did not result in the secretion of type-I IFNs. To confirm the involvement of the LPS-mediated production of type-I IFNs in the observed diminution of HIV-1 production in IM-MDDCs, we performed studies with B18R, a vaccinia virus-derived soluble receptor that blocks the effect of biologically functional type-I IFNs (e.g. IFNα, IFNβ and IFNω). Results depicted in Fig. 8B indicate that the TLR4-mediated reduction in de novo virus production seen in IM-MDDCs was indeed associated with secretion of type-I IFNs.


TLR2 and TLR4 triggering exerts contrasting effects with regard to HIV-1 infection of human dendritic cells and subsequent virus transfer to CD4+ T cells.

Thibault S, Fromentin R, Tardif MR, Tremblay MJ - Retrovirology (2009)

TLR4-mediated decrease in de novo virus production involves type-I IFNs. A) IM-MDDCs were either left untreated (mock) or stimulated for 6 hours with the listed TLR ligands. Cell-free supernatants were harvested and the levels of IFNα/β were quantified through the use of HEK-Blue™ IFNα/β cells. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor. B) IM-MDDCs were either left untreated (mock) or stimulated for 2 hours with the TLR4 ligand LPS. Cells were then washed twice, pulsed with NL4-3/Balenv and cultured in absence or presence of B18R (0.1 μg/ml). Supernatants were harvested at 72 hours post-infection and the viral content was evaluated by a p24 test. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor and are representative of 4 different donors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691729&req=5

Figure 8: TLR4-mediated decrease in de novo virus production involves type-I IFNs. A) IM-MDDCs were either left untreated (mock) or stimulated for 6 hours with the listed TLR ligands. Cell-free supernatants were harvested and the levels of IFNα/β were quantified through the use of HEK-Blue™ IFNα/β cells. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor. B) IM-MDDCs were either left untreated (mock) or stimulated for 2 hours with the TLR4 ligand LPS. Cells were then washed twice, pulsed with NL4-3/Balenv and cultured in absence or presence of B18R (0.1 μg/ml). Supernatants were harvested at 72 hours post-infection and the viral content was evaluated by a p24 test. The data shown represent the mean ± standard deviations of quadruplicate samples from a single donor and are representative of 4 different donors.
Mentions: Knowing that TLR4 stimulation can lead to secretion of type-I IFNs (i.e. IFNα and IFNβ), we next wanted to see whether the observed TLR4-dependent diminution in virus replication was attributable to these antiviral agents. To demonstrate the participation of type-I IFNs in the LPS-dependent modulatory effect on virus production in IM-MDDCs, we performed experiments with HEK-Blue™ IFNα/β indicator cells. Results depicted in Fig. 8A indicate that the TLR4 ligand LPS acted as a strong inducer of IFNα/β in IM-MDDCs while TLR2, 5, 7 and 9 triggering did not result in the secretion of type-I IFNs. To confirm the involvement of the LPS-mediated production of type-I IFNs in the observed diminution of HIV-1 production in IM-MDDCs, we performed studies with B18R, a vaccinia virus-derived soluble receptor that blocks the effect of biologically functional type-I IFNs (e.g. IFNα, IFNβ and IFNω). Results depicted in Fig. 8B indicate that the TLR4-mediated reduction in de novo virus production seen in IM-MDDCs was indeed associated with secretion of type-I IFNs.

Bottom Line: Recognition of microbial products through Toll-like receptors (TLRs) initiates inflammatory responses orchestrated by innate immune cells such as dendritic cells (DCs).No noticeable and consistent effect was observed following engagement of TLR5, 7 and 9.Additional studies indicated that both HIV-1 infection of DCs and DC-mediated virus transmission to CD4+ T cells were reduced upon TLR4 triggering due to secretion of type-I interferons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculté de Médecine, Université Laval, Québec, Canada. sandra.thibault@crchul.ulaval.ca

ABSTRACT

Background: Recognition of microbial products through Toll-like receptors (TLRs) initiates inflammatory responses orchestrated by innate immune cells such as dendritic cells (DCs). As these cells are patrolling mucosal surfaces, a portal of entry for various pathogens including human immunodeficiency virus type-1 (HIV-1), we investigated the impact of TLR stimulation on productive HIV-1 infection of DCs and viral spreading to CD4+ T cells.

Results: We report here that engagement of TLR2 on DCs increases HIV-1 transmission toward CD4+ T cells by primarily affecting de novo virus production by DCs. No noticeable and consistent effect was observed following engagement of TLR5, 7 and 9. Additional studies indicated that both HIV-1 infection of DCs and DC-mediated virus transmission to CD4+ T cells were reduced upon TLR4 triggering due to secretion of type-I interferons.

Conclusion: It can thus be proposed that exposure of DCs to TLR2-binding bacterial constituents derived, for example, from pathogens causing sexually transmissible infections, might influence the process of DC-mediated viral dissemination, a phenomenon that might contribute to a more rapid disease progression.

Show MeSH
Related in: MedlinePlus