Changes in HIV-1 Reservoir Dynamics After Mpox Infection.

In May 2022, a large outbreak of monkeypox virus (MPXV) occurred in several non-endemic regions worldwide. Another outbreak in 2024 raised global concerns, particularly for immunocompromised individuals like people with HIV (PWH). Since the latent HIV-1 reservoir remains a major barrier to a cure, we investigated how past mpox infection affected reservoir dynamics in this population. PWH who had mpox at an average of 9 months before sampling showed a significantly smaller HIV-1 reservoir than MPXV-unexposed PWH. This reduction was accompanied by enhanced antigen-driven proviral reactivation in CD4+ T cells, especially central memory cells (TCM), and increased expression of T-cell activation and proliferation markers like CD32 and Ki67. Mpox also induced sustained immune stress, as reflected by a prolonged decrease in CD4+ T naïve (TN) cells, increased expression of immune senescence and exhaustion markers like PD-1, LAG-3, and CD57, as well as metabolic dysfunction in CD4+ TN and TCM cells, which showed impaired glucose uptake and reduced proliferative capacity. These findings suggest that MPXV-induced immune activation leads to long-lasting changes in T-cell homeostasis and reprograms the HIV-1 reservoir, which may have implications for monitoring immune competence and vaccine responses in this population. Understanding the interplay between HIV-1/MPXV co-infection, T-cell dynamics, and HIV-1 reservoir modulation provides novel insights into how controlled proviral reactivation may inform the design of cure-oriented strategies.