<p>Sensitivity indices of parameters influencing <i>R</i>₀.</p>

the 2022 global monkeypox (Mpox) outbreak revealed sexual transmission as the dominant mode of spread, disproportionately affecting men who have sex with men (MSM) and creating novel challenges in HIV-endemic populations. We present the first mechanistic model capturing bidirectional HIV-Mpox interactions, incorporating three critical innovations: (1) HIV-induced immunological modulation of Mpox progression, (2) antiretroviral therapy (ART)-dependent transmission rates, and (3) vaccination stratification by HIV status. Our analysis demonstrates that HIV co-infection generates a backward bifurcation (critical threshold ), enabling Mpox persistence even when R₀ < 1, a phenomenon absent in single-pathogen models. The model reveals that untreated HIV increases Mpox susceptibility by 2.3-fold (95% CI: 2.1-2.6), while current vaccination strategies show 38% reduced efficacy in advanced HIV cases (CD4+ < 200 cells/mm³). Crucially, we identify an optimal intervention window where 60% ART coverage combined with targeted vaccination reduces co-infection prevalence by 5.7-fold (95% CI: 5.2-6.3) compared to isolated approaches. These findings resolve three key gaps in the 2022 response: (i) lack of co-infection-specific transmission metrics, (ii) unquantified ART-vaccination synergies, and (iii) HIV-stratified vaccine efficacy estimates. Our results provide a framework for integrated HIV-Mpox control, demonstrating that coordinated testing and prevention campaigns outperform sequential interventions by 21–34% across epidemiological scenarios.