People with HIV-1 have higher risk for rejection after kidney transplantation but the mechanism is poorly understood. As HIV latency promotes immune dysregulation and chronic inflammation, we evaluated whether the size of the HIV latent viral reservoir (LVR) at baseline and through 52-weeks is associated with rejection in kidney transplant recipients with HIV from donors with and without HIV. Using the intact proviral DNA assay, we found no differences in the LVR between those who experienced rejection (n = 14) versus those who did not (N = 55) regardless of donor HIV status. These data support the feasibility of HIV+ to HIV+ organ transplantation. Clinical Trials Registration. NCT03500315.

Innate lymphoid cells (ILCs) are rare tissue-resident lymphocytes that functionally mirror cells of CD4+ T helper lineage but lack antigen receptors. Type 3 ILCs (ILC3s) are enriched at barrier sites, regulating inflammation and promoting tissue integrity. Here we profile the promoter-anchored chromosomal contacts of primary human ILC3s using low-input, high-resolution targeted chromosome conformation capture and compare them with those in CD4+ T cells. We use these data to link Crohn's disease genome-wide association study variants with target genes, implicating both known and unanticipated candidates, including CLN3, a causal gene for Batten disease. We show that Cln3 overexpression in a mouse ILC3-like cell line alters stimulation-induced transcriptional programs and cytokine secretion. Extending our approach to five additional immune genome-wide association study traits reveals enrichment for regulators of ILC3 activation. Our work develops methods, maps long-range gene regulation in ILC3s, and prioritizes immune disease risk genes with roles in this clinically relevant immune cell type.

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 (r2 = 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).