Abstract: HEV is the most causative agent of acute viral hepatitis globally. HEV causes acute, chronic,
and extrahepatic manifestations. Chronic HEV infection develops in immunocompromised patients
such as organ transplant patients, HIV-infected patients, and leukemic patients. The source of chronic
HEV infection is not known. Also, the source of extrahepatic manifestations associated with HEV
infection is still unclear. Hepatotropic viruses such as HCV and HBV replicate in peripheral blood
mononuclear cells (PBMCs) and these cells become a source of chronic reactivation of the infections
in allograft organ transplant patients. Herein, we reported that PBMCs and bone marrow-derived
macrophages (BMDMs), isolated from healthy donors (n = 3), are susceptible to HEV in vitro.
Human monocytes (HMOs), human macrophages (HMACs), and human BMDMs were challenged
with HEV-1 and HEV-3 viruses. HEV RNA was measured by qPCR, the marker of the intermediate
replicative form (ds-RNA) was assessed by immunofluorescence, and HEV capsid protein was
assessed by flow cytometry and ELISA. HEV infection was successfully established in primary HMOs,
HMACs, and human BMDMs, but not in the corresponding cells of murine origin. Intermediate
replicative form (ds RNA) was detected in HMOs and HMACs challenged with HEV. The HEV
load was increased over time, and the HEV capsid protein was detected intracellularly in the
HEV-infected cells and accumulated extracellularly over time, confirming that HEV completes the
life cycle inside these cells. The HEV particles produced from the infected BMDMs were infectious
to naive HMOs in vitro. The HEV viral load was comparable in HEV-1- and HEV-3-infected cells,
but HEV-1 induced more inflammatory responses. In conclusion, HMOs, HMACs, and human
BMDMs are permissive to HEV infection and these cells could be the source of chronic and recurrent
infection, especially in immunocompromised patients. Replication of HEV in human BMDMs could
be related to hematological disorders associated with extrahepatic manifestations.