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Activation-induced resistance of human macrophages to HIV-1 infection in vitro
G Zybarth1, N Reiling, H Schmidtmayerova
1The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Abstract:
Cells of the monocyte/macrophage lineage are the first targets of HIV-1 in patients and also serve as reservoirs for the virus during the course of infection. We investigated the effects of cell activation on early events of HIV-1 infection of monocyte-derived macrophages. Addition of LPS, a potent stimulator of macrophages, at the time of infection stimulated entry of HIV-1 into monocyte-derived macrophages, as judged by accumulation of early products of RT, but inhibited the synthesis of late RT products and strongly repressed nuclear import of the viral DNA, resulting in protection from infection. This effect was mediated by the CD14 receptor and involved activation of the p38 mitogen-activated protein kinase pathway. Disruption of this signaling pathway using a specific inhibitor of the p38 mitogen-activated protein kinase (SB203580) restored HIV-1 infection in the presence of LPS. These results suggest a novel view of the role of macrophage activation in anti-HIV responses of the immune system.
Insights
Macrophage activation by LPS initially aids HIV-1 entry but ultimately blocks infection by inhibiting viral DNA nuclear import via the p38 MAPK pathway.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Monocytes and macrophages are primary targets and reservoirs for Human Immunodeficiency Virus type 1 (HIV-1).
- Understanding how cell activation influences HIV-1 infection dynamics is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the impact of macrophage activation on early HIV-1 infection events.
- To elucidate the molecular mechanisms underlying HIV-1 restriction in activated macrophages.
Main Methods:
- Monocyte-derived macrophages were treated with lipopolysaccharide (LPS) during HIV-1 infection.
- Reverse transcriptase (RT) products and viral DNA nuclear import were assessed.
- The role of the CD14 receptor and p38 mitogen-activated protein kinase (MAPK) pathway was examined using specific inhibitors.
Main Results:
- LPS stimulation enhanced early HIV-1 entry but inhibited late RT products and viral DNA nuclear import.
- This protective effect was mediated through the CD14 receptor and p38 MAPK pathway activation.
- Inhibiting p38 MAPK with SB203580 reversed LPS-induced protection, restoring HIV-1 infection.
Conclusions:
- Macrophage activation presents a novel mechanism for anti-HIV-1 defense.
- Targeting the CD14/p38 MAPK pathway could offer new therapeutic avenues against HIV-1 infection.