biostudies-literatureStampfer SDNational Institute of Allergy and Infectious Diseases Division of Intramural ResearchEmory University School of MedicineNIAID NIH HHSNational Institutes of HealthNIH HHSCenter for AIDS Research, Emory UniversityOffice of Research Infrastructure Programs116501https://www.ebi.ac.uk/biostudies/studies/S-EPMC12880552biostudies-literatureUnknown44(11)The 2022 mpox virus (MPXV) outbreak caused life-threatening mpox disease in people living with HIV (PLWH). We compared immune responses to MPXV in PLWH who were either mpox-naive or were mpox survivors. We characterized the magnitude, polyfunctionality, and cytolytic potential of CD4 and CD8 T cells specific to MPXV and cross-reactive orthopoxviral antigens and compared them to HIV- and cytomegalovirus (CMV)-specific T cells. Mpox survivors developed MPXV-specific CD4 T cells capable of producing IFNγ, TNFα, and IL-2. Their polyfunctionality was superior to CMV-specific CD4 T cells. MPXV- and CMV-specific CD8 T cells had similar cytolytic potentials. Importantly, mpox survivors developed strong MPXV-specific antibodies with neutralizing activity. Prior vaccinia or JYNNEOS vaccination was aCell reportsMpox-specific cellular and humoral immunity in mpox survivors living with HIV.PMC12880552P51 OD011132K08 AI180431P30 AI050409Amara RRSette AKelley CFStampfer SDMoriarty MGangadhara SSatheshkumar PSPriyamvada LSheth ANSambyal SGrifoni AfalseMpox-specific cellular and humoral immunity in mpox survivors living with HIV.The 2022 mpox virus (MPXV) outbreak caused life-threatening mpox disease in people living with HIV (PLWH). We compared immune responses to MPXV in PLWH who were either mpox-naive or were mpox survivors. We characterized the magnitude, polyfunctionality, and cytolytic potential of CD4 and CD8 T cells specific to MPXV and cross-reactive orthopoxviral antigens and compared them to HIV- and cytomegalovirus (CMV)-specific T cells. Mpox survivors developed MPXV-specific CD4 T cells capable of producing IFNγ, TNFα, and IL-2. Their polyfunctionality was superior to CMV-specific CD4 T cells. MPXV- and CMV-specific CD8 T cells had similar cytolytic potentials. Importantly, mpox survivors developed strong MPXV-specific antibodies with neutralizing activity. Prior vaccinia or JYNNEOS vaccination was a2025-01-01T00:00:00Z2025 Nov2026-07-15T06:59:29.197Z2026-06-30T03:35:50.262ZS-EPMC128805524117676410.1016/j.celrep.2025.116501