Human cytomegalovirus reprograms hematopoietic progenitor cells into immunosuppressive monocyte to achieve latency

Abstract The precise cell type hosting latent human cytomegalovirus (HCMV) remains elusive. Here we report that HCMV reprograms human hematopoietic progenitor cells (HPCs) into a unique monocyte subset to achieve latency. Unlike conventional monocytes, this monocyte subset possesses higher levels of B7-H4, IL-10 and iNOS, longer lifespan and strong immunosuppressive capacity. Cell sorting of peripheral blood from latently infected human donors confirms that only this monocyte subset, representing less than 0.1% of peripheral mononuclear cells, is HCMV genome-positive but immediate-early (IE)-negative. Mechanistic studies demonstrate that HCMV promotes the differentiation of HPCs into this monocyte subset by activating cellular signal transducer and activator of transcription 3 (STAT3). In turn, this monocyte subset generates high level of nitric oxide (NO) to silence HCMV IE transcription and promote viral latency. By contrast, US28-knockout HCMV mutant incapable of activating STAT3, fails to reprogram the HPCs and achieve latency. Our findings reveal that HCMV differentiates human HPCs into long-life, immunosuppressive monocyte subset for viral latency via activating STAT3/iNOS/NO axis.