MPXV replication and drug resistance in CNS of advanced HIV case at autopsy.

Monkeypox virus (MPXV) clade IIb caused an outbreak of >100,000 cases globally, with highest disease burden in people living with advanced human immunodeficiency virus (HIV), those with CD4 count <200 cells/mm3. We performed an extensive autopsy on a fatal case of mpox in a person living with advanced HIV-1, who achieved HIV suppression but poor immune reconstitution despite > 6 months antiretroviral therapy and had progressive necrotizing mucocutaneous mpox disease despite multiple prolonged mpox-targeted therapies. We quantified MPXV DNA across 76 tissues and observed a high burden in skin and mucosal tissue and a lower burden in all central nervous system (CNS) tissues tested. However, we detected replication-competent MPXV in multiple CNS tissues and confirmed neuronal and glial cell infection using RNA-scope in situ hybridization. MPVX sequencing from body and brain tissues revealed widespread tecovirimat resistance-associated variants. This case proves that replication-competent MPXV and tecovirimat resistance-associated isolates can infect and persist in the CNS of people with advanced HIV thus informing future therapeutic design.