Identification of inducible HIV reservoirs in tonsillar, intestinal and cervical tissue models of HIV latency
HIV persists in diverse tissues, with distinct cellular reservoirs presenting a major barrier to a cure and requiring targeted therapeutic strategies to address this heterogeneity. Here, we develop tissue models of HIV latency using human tonsillar, intestinal and cervicovaginal tissues. These models reveal differential HIV infection across CD4<sup>+</sup> T-cell subpopulations, with ART partially restoring CD4<sup>+</sup> T cells and reducing intact HIV DNA. T follicular helper cells (T<sub>FH CD69+ CCR7-</sub>) are the primary inducible reservoir in tonsils, while tissue-resident memory cells (T<sub>RM CD69+ CD49a+</sub>) dominate in the intestine. Identification of markers for inducible reservoirs shows that CD69, CD45RO, and PD-1 are shared across tissues, while CXCR5 in tonsils and CD49a in the intestine act as tissue-specific markers. Furthermore, using different latency reversal agents (LRAs) demonstrates that Histone Deacetylase Inhibitors (HDACis) fail to induce HIV in any tissue, the SMAC mimetic AZD5582 is effective only in a resident-memory CD4<sup>+</sup> T-cell subpopulation in the intestine, and IL-15 exhibits the broadest reactivation potential across tissues and CD4<sup>+</sup> T-cell subsets. These models provide insights into the inducible reservoir's composition in different tissues and inform strategies for its elimination.
Authors
- Cristina Mancebo-Pérez (ORCID: https://orcid.org/0000-0001-5960-5168)
- L. Mañalich (ORCID: https://orcid.org/0000-0002-4624-4671)
- Ana Gallego-Cortés (ORCID: https://orcid.org/0000-0001-5126-600X)
- Nerea Sánchez-Gaona (ORCID: https://orcid.org/0000-0003-1977-8691)
- María J. Buzón (ORCID: https://orcid.org/0000-0003-4427-9413)
- I Llano
- Enrique Martín‐Gayo (ORCID: https://orcid.org/0000-0002-2619-6086)
- Júlia G. Prado (ORCID: https://orcid.org/0000-0002-5439-4645)
- Vicenç Falcó (ORCID: https://orcid.org/0000-0001-9626-0023)
- Nuria Ortiz (ORCID: https://orcid.org/0009-0009-2939-7201)
- Juan Lorente (ORCID: https://orcid.org/0000-0002-3264-0251)
- Stefania Landolfi (ORCID: https://orcid.org/0000-0002-1059-635X)
- Josep Castellví (ORCID: https://orcid.org/0000-0001-5745-9996)
- Meritxell Genescà (ORCID: https://orcid.org/0000-0001-6413-3812)
- Aleix Benítez-Martínez (ORCID: https://orcid.org/0009-0003-7252-3564)
- Félix Pumarola (ORCID: https://orcid.org/0000-0002-7914-1695)
- O. Ruiz-Isant (ORCID: https://orcid.org/0009-0005-6582-2675)
Institutions
- Instituto de Salud Carlos III (ES)
- IrsiCaixa (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Centro de Investigación Biomédica en Red (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Hospital Universitario de La Princesa (ES)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Centro de Biología Molecular Severo Ochoa (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41467-025-65288-9
- Citations
- 4
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.15
Funders
- Gilead Sciences
- Ministerio de Economía y Competitividad
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación