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

Abstract

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.