iPS cell-derived model to study the interaction between tissue macrophage and HIV-1
Youssef M Eltalkhawy1, Naofumi Takahashi1, Yasuo Ariumi1
1Joint Research Center for Human Retrovirus Infection, Kumamoto University, Honjo 2-2-1, Kumamoto-city, Kumamoto 860-0811, Japan.
Abstract:
Despite effective antiretroviral therapy, HIV-1 persists in cells, including macrophages, which is an obstacle to cure. However, the precise role of macrophages in HIV-1 infection remains unclear because they reside in tissues that are not easily accessible. Monocyte-derived macrophages are widely used as a model in which peripheral blood monocytes are cultured and differentiated into macrophages. However, another model is needed because recent studies revealed that most macrophages in adult tissues originate from the yolk sac and fetal liver precursors rather than monocytes, and the embryonic macrophages possess a self-renewal (proliferating) capacity that monocyte-derived macrophages lack. Here, we show that human induced pluripotent stem cell-derived immortalized macrophage-like cells are a useful self-renewing macrophage model. They proliferate in a cytokine-dependent manner, retain macrophage functions, support HIV-1 replication, and exhibit infected monocyte-derived macrophage-like phenotypes, such as enhanced tunneling nanotube formation and cell motility, as well as resistance to a viral cytopathic effect. However, several differences are also observed between monocyte-derived macrophages and induced pluripotent stem cell-derived immortalized macrophage-like cells, most of which can be explained by the proliferation of induced pluripotent stem cell-derived immortalized macrophage-like cells. For instance, proviruses with large internal deletions, which increased over time in individuals receiving antiretroviral therapy, are enriched more rapidly in induced pluripotent stem cell-derived immortalized macrophage-like cells. Interestingly, inhibition of viral transcription by HIV-1-suppressing agents is more obvious in induced pluripotent stem cell-derived immortalized macrophage-like cells. Collectively, our present study proposes that the model of induced pluripotent stem cell-derived immortalized macrophage-like cells is suitable for mimicking the interplay between HIV-1 and self-renewing tissue macrophages, the newly recognized major population in most tissues that cannot be fully modeled by monocyte-derived macrophages alone.
Insights
Researchers developed a new self-renewing macrophage model using induced pluripotent stem cells. This model effectively mimics HIV-1 interactions in tissue macrophages, offering new insights beyond traditional monocyte-derived models for HIV-1 persistence research.
Area of Science:
- Immunology
- Virology
- Stem Cell Biology
Background:
- Human Immunodeficiency Virus type 1 (HIV-1) persistence in macrophages hinders curative strategies.
- Current macrophage models, like monocyte-derived macrophages, do not fully represent tissue-resident macrophages, which originate from embryonic precursors and possess self-renewal capacity.
Purpose of the Study:
- To establish and validate a novel self-renewing macrophage model using human induced pluripotent stem cell-derived immortalized macrophage-like cells.
- To investigate the utility of this new model in studying HIV-1 replication and persistence, particularly in comparison to monocyte-derived macrophages.
Main Methods:
- Generation of immortalized macrophage-like cells from human induced pluripotent stem cells.
- Culture and differentiation of cells, cytokine-dependent proliferation assays.
- Assessment of macrophage functions, HIV-1 replication assays, and analysis of viral genetic material.
- Comparison of cellular phenotypes and viral dynamics with monocyte-derived macrophages.
Main Results:
- Induced pluripotent stem cell-derived immortalized macrophage-like cells demonstrated cytokine-dependent proliferation and retained key macrophage functions.
- These cells supported HIV-1 replication and exhibited phenotypes similar to infected monocyte-derived macrophages, including enhanced cell motility and resistance to viral cytopathic effects.
- Differences observed, such as faster enrichment of proviruses with deletions and enhanced inhibition of viral transcription, were linked to the proliferative capacity of the new model.
Conclusions:
- Human induced pluripotent stem cell-derived immortalized macrophage-like cells provide a valuable model for studying self-renewing tissue macrophages.
- This model offers a more accurate representation of HIV-1 interplay with tissue-resident macrophages than monocyte-derived macrophages alone.
- The model facilitates research into HIV-1 persistence mechanisms within self-renewing macrophage populations, crucial for developing effective cure strategies.
