Durable but impaired humoral and cellular immune responses against monkeypox virus in people with HIV over 18 months

Monkeypox virus (MPXV), a zoonotic orthopoxvirus (OPXV), re-emerged as a global public health concern following the 2022 multi-country outbreak that disproportionately affected people with human immunodeficiency virus (HIV). In July 2023, the U.S. National Institutes of Health classified MPXV as an AIDS-defining opportunistic infection, underscoring the urgency of understanding immune features in immunocompromised populations. Existing studies provide limited data on the durability and coordination of MPXV-specific humoral and cellular immunity in people with HIV (PWH). Moreover, whether concomitant MPXV infection modulates HIV-specific immunity in PWH remains unclear. We aimed to evaluate the durability of immune responses against MPXV, compare immune profiles between PWH and people without HIV (PWoH), and assess the impact of MPXV coinfection on HIV-specific immunity. We conducted a prospective immunological analysis involving 28 PWH and 13 PWoH with confirmed MPXV infection. Peripheral blood samples were collected at 1–2 weeks, 1–6 months, and 12–18 months post-infection. Plasma IgG levels against MPXV antigens were measured using ELISA. Poxvirus- and HIV-specific memory T (Tm) cell responses were assessed using activation-induced marker and intracellular cytokine staining assays via flow cytometry. MPXV infection elicited durable humoral and cellular immune responses for up to 18 months, regardless of HIV status. However, PWH demonstrated attenuated MPXV-specific antibody responses, lower frequencies of poxvirus-specific Tm cells, and reduced polyfunctionality compared to PWoH. Notably, immune coordination in PWH was impaired, as evidenced by weakened concordance between humoral and cellular responses, disrupted interactions between CD4+ and CD8+ Tm cell subsets, and diminished consistency among antibody levels. Additionally, HIV-specific Tm cell responses remained stable in antiretroviral-treated PWH, irrespective of prior MPXV infection. MPXV infection induced long-lasting cellular and humoral immunity in both PWH and PWoH. However, HIV-mediated immune dysregulation compromised the strength and coordination of these responses.