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Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice

HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and per...

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Autores principales: Weichseldorfer, Matthew, Affram, Yvonne, Heredia, Alonso, Rikhtegaran-Tehrani, Zahra, Sajadi, Mohammad M., Williams, Sumiko P., Tagaya, Yutaka, Benedetti, Francesca, Ramadhani, Habib O., Denaro, Frank, Munawwar, Arshi, Bryant, Joseph, Zella, Davide, Reitz, Marvin, Romerio, Fabio, Latinovic, Olga S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557591/
https://www.ncbi.nlm.nih.gov/pubmed/34717655
http://dx.doi.org/10.1186/s12967-021-03120-w
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author Weichseldorfer, Matthew
Affram, Yvonne
Heredia, Alonso
Rikhtegaran-Tehrani, Zahra
Sajadi, Mohammad M.
Williams, Sumiko P.
Tagaya, Yutaka
Benedetti, Francesca
Ramadhani, Habib O.
Denaro, Frank
Munawwar, Arshi
Bryant, Joseph
Zella, Davide
Reitz, Marvin
Romerio, Fabio
Latinovic, Olga S.
author_facet Weichseldorfer, Matthew
Affram, Yvonne
Heredia, Alonso
Rikhtegaran-Tehrani, Zahra
Sajadi, Mohammad M.
Williams, Sumiko P.
Tagaya, Yutaka
Benedetti, Francesca
Ramadhani, Habib O.
Denaro, Frank
Munawwar, Arshi
Bryant, Joseph
Zella, Davide
Reitz, Marvin
Romerio, Fabio
Latinovic, Olga S.
author_sort Weichseldorfer, Matthew
collection PubMed
description HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus, appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed us to identify specific solid tissue reservoirs of human T cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34+ humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-021-03120-w.
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spelling pubmed-85575912021-11-03 Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice Weichseldorfer, Matthew Affram, Yvonne Heredia, Alonso Rikhtegaran-Tehrani, Zahra Sajadi, Mohammad M. Williams, Sumiko P. Tagaya, Yutaka Benedetti, Francesca Ramadhani, Habib O. Denaro, Frank Munawwar, Arshi Bryant, Joseph Zella, Davide Reitz, Marvin Romerio, Fabio Latinovic, Olga S. J Transl Med Research HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus, appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed us to identify specific solid tissue reservoirs of human T cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34+ humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-021-03120-w. BioMed Central 2021-10-30 /pmc/articles/PMC8557591/ /pubmed/34717655 http://dx.doi.org/10.1186/s12967-021-03120-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Weichseldorfer, Matthew
Affram, Yvonne
Heredia, Alonso
Rikhtegaran-Tehrani, Zahra
Sajadi, Mohammad M.
Williams, Sumiko P.
Tagaya, Yutaka
Benedetti, Francesca
Ramadhani, Habib O.
Denaro, Frank
Munawwar, Arshi
Bryant, Joseph
Zella, Davide
Reitz, Marvin
Romerio, Fabio
Latinovic, Olga S.
Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice
title Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice
title_full Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice
title_fullStr Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice
title_full_unstemmed Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice
title_short Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice
title_sort combined cart including tenofovir disoproxil, emtricitabine, and dolutegravir has potent therapeutic effects in hiv-1 infected humanized mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557591/
https://www.ncbi.nlm.nih.gov/pubmed/34717655
http://dx.doi.org/10.1186/s12967-021-03120-w
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