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Myeloid Derived Suppressor Cells Expansion Persists After Early ART and May Affect CD4 T Cell Recovery
Chiara Agrati1, Nicola Tumino1, Veronica Bordoni1
1Cellular Immunology Laboratory, National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy.
Abstract:
Myeloid-derived suppressor cells (MDSC) are expanded during HIV-1 infection and correlated with disease progression. MDSC expand in the early phase of primary infection depending on TRAIL level. In this study we evaluated the effect of ART on the frequency of MDSC in patients with primary HIV infection (PHI), and their impact on CD4 T cell reconstitution. MDSC frequency was evaluated by flow-cytometry in 60 PHI patients at 12, 24 and 48 weeks after ART initiation. Cytokine plasma levels were evaluated by Luminex technology at the same time points. The capacity of MDSC to modulate hematopoietic early progenitor cells' expansion was evaluated using the OP9/Dl1 in vitro system. As previously described, polymorphonuclear-MDSC (PMN-MDSC) frequency was higher in PHI compared to healthy donors. Interestingly, 48 weeks of successful ART failed to normalize the PMN-MDSC frequency. Moreover, PMN-MDSC frequency was not correlated with residual viral load, suggesting that the persistence of PMN-MDSC was not due to residual viral replication. Interestingly, patients with low PMN-MDSC frequency (<6%) at T0 had a higher HIV DNA at the same time point than individuals with high PMN-MDSC frequency (>6%). We also found an inverse correlation between PMN-MDSC frequency and CD4-T cell count at 48 weeks post-ART, which was confirmed by multivariate analysis adjusting for age and CD4 T cell number at baseline. These data suggest that the persistence of PMN-MDSC may impact CD4 T cell recovery. Indeed, in vitro PMN-MDSC impaired the expansion of CD34+CD38- hematopoietic early progenitors. Further, a balance between TRAIL and GM-CSF may be necessary to maintain a low MDSC level. In conclusion, early ART initiation was not able to normalize PMN-MDSC frequency that might impact the CD4 T cell recovery. These data open new questions regarding the clinical impact of MDSC persistence in HIV+ patients, in particular on non-AIDS related diseases.
Insights
Antiretroviral therapy (ART) does not normalize myeloid-derived suppressor cells (MDSC) in primary HIV infection. Persistent MDSC may hinder CD4 T cell recovery and impact non-AIDS related diseases in HIV patients.
Area of Science:
- Immunology
- Virology
- Hematology
Background:
- Myeloid-derived suppressor cells (MDSC) are elevated in HIV-1 infection and linked to disease progression.
- MDSC expansion during primary HIV infection (PHI) is influenced by TRAIL levels.
Purpose of the Study:
- To assess the impact of ART on MDSC frequency in PHI patients.
- To investigate the relationship between MDSC and CD4 T cell reconstitution.
- To explore the role of MDSC in hematopoietic progenitor cell expansion.
Main Methods:
- Flow cytometry to quantify MDSC in 60 PHI patients over 48 weeks of ART.
- Luminex technology to measure plasma cytokine levels.
- In vitro OP9/Dl1 system to evaluate MDSC's effect on hematopoietic progenitor cells.
Main Results:
- Polymorphonuclear-MDSC (PMN-MDSC) remained elevated in PHI patients even after 48 weeks of ART.
- PMN-MDSC frequency did not correlate with residual viral load.
- Higher PMN-MDSC levels inversely correlated with CD4 T cell count recovery post-ART.
- In vitro, PMN-MDSC impaired hematopoietic progenitor cell expansion.
Conclusions:
- Early ART initiation does not normalize PMN-MDSC frequency in PHI.
- Persistent PMN-MDSC may impede CD4 T cell recovery.
- MDSC persistence may have clinical implications for non-AIDS related diseases in HIV+ individuals.
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