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Latency reversal agents affect differently the latent reservoir present in distinct CD4+ t subpopulations
Grau Expósito, Judith (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Luque-Ballesteros, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Navarro, Jordi (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Curran, Adrian (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Burgos, Joaquín (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ribera, Esteban (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Torrella Domingo, Adriana (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Planas, Bibiana (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Badía, Rosa (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martin-Castillo, Mario (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernández-Sojo, Jesús (Hospital Universitari Vall d'Hebron)
Genescà Ferrer, Meritxell. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Falcó, Vicenç (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Buzón, Maria José (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Fecha: 2019
Resumen: Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4 T cell subsets. We observed that a median of 16. 28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10. 10% of these HIV-1 RNA cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4 T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA cells, in most, but not all, CD4 T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4 T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.
Ayudas: Ministerio de Economía y Competitividad SAF2015-67334-R
Derechos: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Lengua: Anglès
Documento: Article ; recerca ; Versió publicada
Materia: Anti-HIV Agents ; CD4-Positive T-Lymphocytes ; Depsipeptides ; Diterpenes ; HIV Infections ; HIV-1 ; Humans ; Viral Load ; Virus Activation ; Virus Latency
Publicado en: PLOS pathogens, Vol. 15 Núm. 8 (august 2019) , p. e1007991, ISSN 1553-7374

DOI: 10.1371/journal.ppat.1007991
PMID: 31425551


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