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

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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 We observed higher inducible HIV-1 reservoir activity in nine participants from the Dendritic Cell-Tat, Rev, and Nef (DC-TRN) trial who previously experienced viral rebound and subsequently achieved viral re-suppression on long-term ART (p = 0.01). This increase in inducible HIV-1 reservoir activity occurred in the absence of major changes in total or intact proviral DNA (p = 0.99, and p=0.35, respectively). Immune profiling suggested persistent differences in memory T cell phenotypes, after long-term re-suppression on ART, including enrichment of CXCR3-expressing central memory CD4+ T cells that positively correlated with inducible tat/rev msRNA expression (r 2 = 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).

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