Changes in HIV-1 Reservoir Dynamics After Mpox Infection

Abstract

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.