Held, C. | bioRxiv Science

bioRxiv2026

Human cytomegalovirus UL2 is not required for lytic replication or viral latency and reactivation

Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality in transplant patients and is a major cause of congenital disease. Understanding the role of viral genes during infection, viral replication, and viral latency establishment and reactivation is key to the development of new antivirals, which are currently limited. The viral RL11 is a conserved, but understudied viral locus, with previously described roles in specific phases of the viral lifecycle. Antisense to and within the RL11 region are two unrelated genes, including UL2. In this study, we investigate the role of UL2 during viral infection and find that UL2 is not required for lytic replication nor required for viral infection, latency establishment (or persistence) and reactivation in either THP-1 monocytes or primary human hematopoietic progenitor cells (HPCs). As viral genes are evolutionarily optimized for viral fitness, this study suggests that HCMV UL2 has a role outside of viral fitness and may be a unique target or contributor to HCMV-mediated processes including immune response or other viral co-factor regulation.

microbiology↗

bioRxiv2026

Human Cytomegalovirus UL4 is Required for Viral Reactivation via Cellular Reprogramming in Latently Infected CD34+ Progenitor Cells and Humanized Mice

Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality after both solid organ and hematopoietic stem cell transplant, due to bone marrow stem cell engraftment failure, myelosuppression, and immunosuppression. While direct infection and viral replication lead to disease, latent infection in the CD34+ hematopoietic progenitor cell (HPC) pool has direct and indirect effects on hematopoiesis. Studies from several laboratories support the hypothesis that HCMV latency and reactivation are intrinsically linked with the state of the cell. We, and others, have previously demonstrated roles for different viral gene products in regulating both cellular differentiation and the balance between viral latency and reactivation, including the viral RL11 proteins UL7 and UL8. In this study, we show that UL4 is expressed during latency and required for reactivation in HPCs, THP-1 monocytes, and humanized mice. describe both a cell-specific and viral lifecycle-specific role for the RL11 gene UL4 during HCMV infection. Additionally, we demonstrate that UL4 plays specific roles in controlling essential cellular functions including aspects of proliferation and differentiation and immune signaling to assist in establishing a virus-favorable environment in progenitor cells. This study identifies a novel viral reactivation factor that has implications for both viral control and alteration of hematopoiesis in transplant patients.

microbiology↗