Latency reversal agents affect differently the latent reservoir present in distinct CD4+ t subpopulations
| Autor: | Grau-Expósito, Judith, Luque-Ballesteros, Laura, Navarro Mercadé, Jordi, Curran, Adrian, Burgos, Joaquín, Ribera, Esteban, Torrella Domingo, Adriana, Planas, Bibiana, Badía, Rosa, Martin-Castillo, Mario, Fernández-Sojo, Jesús, Genescà Ferrer, Meritxell., Falcó, Vicenç, Buzon, Maria J., Universitat Autònoma de Barcelona |
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| Přispěvatelé: | [Grau-Expósito J, Luque-Ballesteros L, Navarro J, Curran A, Burgos J, Ribera E, Torrella A, Planas B, Badía R, Martin-Castillo M, Genescà M, Falcó V, Buzon MJ] Servei de Malalties Infeccioses, Hospital Universitari Vall d’Hebron, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR). Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. [Fernández-Sojo J] Banc de Sang i Teixits, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2019 |
| Předmět: |
RNA viruses
CD4-Positive T-Lymphocytes Hemic and Immune Systems::Blood::Blood Cells::Leukocytes::Leukocytes Mononuclear::Lymphocytes::T-Lymphocytes::Hemic and Immune Systems::CD4-Positive T-Lymphocytes [ANATOMY] Apoptosis HIV Infections Pathology and Laboratory Medicine Toxicology medicine.disease_cause Microbiological Phenomena::Virus Physiological Phenomena::Virus Latency [PHENOMENA AND PROCESSES] Memory T cells Romidepsin White Blood Cells Immunodeficiency Viruses Animal Cells Depsipeptides Medicine and Health Sciences Biology (General) acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antiinfecciosos::antivíricos::antirretrovirales::fármacos anti-VIH [COMPUESTOS QUÍMICOS Y DROGAS] 0303 health sciences Cell Death T Cells 030302 biochemistry & molecular biology Antiretrovirals Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Anti-HIV Agents [CHEMICALS AND DRUGS] Viral Load Viral Persistence and Latency 3. Good health Virus Latency medicine.anatomical_structure Cèl·lules T Medical Microbiology Cell Processes Viral Pathogens Viruses Pathogens Cellular Types Stem cell Diterpenes Viral load fenómenos microbiológicos::fenómenos fisiológicos de los virus::latencia viral [FENÓMENOS Y PROCESOS] Research Article medicine.drug QH301-705.5 Viral protein Anti-HIV Agents Immune Cells T cell Immunology Biology Microbiology 03 medical and health sciences Virology Retroviruses Genetics medicine Humans Microbial Pathogens Molecular Biology 030304 developmental biology Blood Cells Toxicity Lentivirus Virus - Reproducció Organisms Biology and Life Sciences HIV RNA Cell Biology RC581-607 Viral Replication sistemas sanguíneo e inmunológico::sistemas sanguíneo e inmunológico::sistema inmunológico::leucocitos::leucocitos mononucleares::linfocitos::linfocitos T::linfocitos T CD4-positivos [ANATOMÍA] Viral replication HIV-1 Parasitology Virus Activation Immunologic diseases. Allergy Ex vivo |
| Zdroj: | Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona PLoS Pathogens Scientia PLoS Pathogens, Vol 15, Iss 8, p e1007991 (2019) |
| Popis: | 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. Author summary HIV infection is an incurable disease. Despite antiretroviral therapy, a pool of cells with HIV in a latent state persists and precludes fully eradication of the viral infection. The cells that contain this latent viral reservoir are very diverse, and therefore different therapeutic strategies would be necessary to target and eliminate all infected cells. Latency Reversal Agents (LRAs) are compounds able to awake the latent virus from its dormant state with the purpose of making infected cells visible to the immune system. But the ability of the LRAs to target different cell types containing HIV is currently unknown. Here, using a novel methodology that interrogates individual cells, we found that current LRAs do not impact equally all infected cells. In fact, certain types of memory lymphocytes, recognized to harbor latent HIV for decades, are not fully impacted by most of the LRAs tested. Our study highlights the difficulty to cure HIV with the currently available LRAs. Different therapeutic approaches aimed at reversing HIV latency from diverse cellular reservoirs are needed to reduce HIV persistence. |
| Databáze: | OpenAIRE |
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