HIV-1 reservoir inducibility and immune phenotypes after prolonged analytical treatment interruption: a long-term follow-up study

BACKGROUND: Despite effective suppression of HIV-1 replication by antiretroviral therapy (ART), persistent viral reservoirs prevent cure and necessitate lifelong treatment. While short-term dynamics of HIV-1 rebound following treatment interruption have been extensively studied, the longer-term consequences of immune perturbation and transient viraemia for reservoir quality and immune architecture remain incompletely understood. METHODS: We leveraged a rare historical human cohort that experienced prolonged viral rebound during a dendritic cell-based therapeutic vaccine study as a "perturbation model" to explore HIV-1 reservoir characteristics and immune remodelling more than a decade after ART resumption. We combined functional inducible HIV-1 reservoir measurements with high-dimensional immune phenotyping and included comparator analyses using a separate cohort of eight individuals with sustained ART-mediated suppression. FINDINGS: = 0.54, p = 0.03). INTERPRETATION: Together, these findings suggest that immune perturbation and viral rebound may be associated with persistent changes in HIV-1 reservoir inducibility and immune architecture after viral re-suppression. Our study highlights a possible increase in inducible HIV-1 reservoir activity associated with a CXCR3+ memory T cell phenotype, supporting further evaluation of reservoir quality endpoints, candidate immunophenotypic correlates, and long-term monitoring strategies in contemporary remission trials. FUNDING: This research was supported by grants from Aidsfonds (P-60602, P-263, P-53302, P-53601, P-60804), MRACE (EMC2020-083); Horizon Europe (681032); Health Holland (LSHM19100-SGF and EMCLSH19023), and NWO (ZonMW-40-44600-98-333).