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Flt3L-Mediated Expansion of Plasmacytoid Dendritic Cells Suppresses HIV Infection in Humanized Mice
Tram N Q Pham1, Oussama Meziane1, Mohammad Alam Miah2
1Montréal Clinical Research Institute, Montréal, QC H2W 1R7, Canada.
Abstract:
Plasmacytoid dendritic cells (plasmacytoid DC, pDC) are major IFN-I producers and have been shown to be affected by HIV through ill-defined mechanisms. In this study, we directly assess the role of pDC in early infection, evaluating whether modulating their abundance can alter viral replication. First, HIV infection of humanized mice induces systemic depletion of pDC, and in the presence of soluble FMS-like tyrosine kinase 3 ligand (Flt3L), pDC levels remain elevated. Flt3L significantly delays the onset of viremia and reduces viral replication via a process that is dependent on pDC and mediated through an enhanced early IFN-I response. pDC from Flt3L-treated mice are more prone to express IFN-α following TLR7 stimulation, but this propensity is gradually decreased during infection. In conclusion, maintaining pDC levels and function is key to effective early viral control, and in this context, these findings provide practical insights for anti-HIV strategies and vaccine design.
Insights
Maintaining plasmacytoid dendritic cell (pDC) levels delays HIV replication. Enhancing pDC function with Flt3L boosts early IFN-I responses, crucial for viral control in early HIV infection.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- Plasmacytoid dendritic cells (pDCs) are key producers of Type I Interferon (IFN-I).
- HIV infection impacts pDCs through poorly understood mechanisms.
- Understanding pDC roles in early HIV infection is critical for therapeutic strategies.
Purpose of the Study:
- To investigate the role of pDCs in early HIV infection.
- To determine if modulating pDC abundance affects viral replication.
- To evaluate the potential of FMS-like tyrosine kinase 3 ligand (Flt3L) in controlling HIV.
Main Methods:
- Utilized humanized mouse models of HIV infection.
- Administered soluble FMS-like tyrosine kinase 3 ligand (Flt3L) to modulate pDC levels.
- Assessed pDC abundance, IFN-I production, and viral replication (viremia).
- Investigated pDC IFN-α expression following TLR7 stimulation.
Main Results:
- HIV infection caused systemic pDC depletion in mice.
- Flt3L administration maintained elevated pDC levels.
- Flt3L treatment significantly delayed viremia onset and reduced viral replication.
- pDCs from Flt3L-treated mice showed enhanced early IFN-I response, crucial for viral control.
- pDC IFN-α production capacity decreased over the course of infection.
Conclusions:
- Maintaining pDC levels and function is vital for early HIV control.
- Flt3L enhances early IFN-I responses mediated by pDCs, offering a potential anti-HIV strategy.
- These findings provide insights for developing novel anti-HIV therapies and vaccine designs.
