iPS cell-derived model to study the interaction between tissue macrophage and HIV-1

Abstract Despite effective antiretroviral therapy (ART), 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 (MDMs) 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 MDMs lack. Here, we show that human induced pluripotent stem (iPS) cell-derived immortalized macrophage-like cells (iPS-ML) are a useful self-renewing macrophage model. They proliferate in a cytokine-dependent manner, retain macrophage functions, support HIV-1 replication, and exhibit infected MDM-like phenotypes, such as enhanced tunneling nanotube formation and cell motility, and resistance to viral cytopathic effect. However, several differences are also observed between MDMs and iPS-ML, most of which can be explained by the proliferation of iPS-ML. For instance, proviruses with large internal deletions, which increased over time in individuals receiving ART, are enriched more rapidly in iPS-ML. Interestingly, inhibition of viral transcription by HIV-1-suppressing agents is more obvious in iPS-ML. Collectively, our present study proposes that iPS-ML model 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 MDMs alone.