An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients

Celsa A Spina, Jenny Anderson, Nancie M Archin, Alberto Bosque, Jonathan Chan, Marylinda Famiglietti, Warner Green, Angela Kashuba, Sharon R Lewin, David M Margolis, Matthew Mau, Debbie Ruelas, Suha Saleh, Kotaro Shirakawa, Robert F Siliciano, Akul Singhania, Paula Soto, Valeri H Terry, Eric Verdin, Christopher Woelk & 3 others Stacey Wooden, Sifei Xing, Vicente Planelles

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Abstract

The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for ?anti-latency? therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.
Original languageEnglish
Article numbere1003834
Number of pages15
JournalPLoS Pathogens
Volume9
Issue number12
DOIs
Publication statusPublished - 2013

Cite this

Spina, C. A., Anderson, J., Archin, N. M., Bosque, A., Chan, J., Famiglietti, M., ... Planelles, V. (2013). An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathogens, 9(12), [e1003834]. https://doi.org/10.1371/journal.ppat.1003834
Spina, Celsa A ; Anderson, Jenny ; Archin, Nancie M ; Bosque, Alberto ; Chan, Jonathan ; Famiglietti, Marylinda ; Green, Warner ; Kashuba, Angela ; Lewin, Sharon R ; Margolis, David M ; Mau, Matthew ; Ruelas, Debbie ; Saleh, Suha ; Shirakawa, Kotaro ; Siliciano, Robert F ; Singhania, Akul ; Soto, Paula ; Terry, Valeri H ; Verdin, Eric ; Woelk, Christopher ; Wooden, Stacey ; Xing, Sifei ; Planelles, Vicente. / An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. In: PLoS Pathogens. 2013 ; Vol. 9, No. 12.
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abstract = "The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for ?anti-latency? therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.",
author = "Spina, {Celsa A} and Jenny Anderson and Archin, {Nancie M} and Alberto Bosque and Jonathan Chan and Marylinda Famiglietti and Warner Green and Angela Kashuba and Lewin, {Sharon R} and Margolis, {David M} and Matthew Mau and Debbie Ruelas and Suha Saleh and Kotaro Shirakawa and Siliciano, {Robert F} and Akul Singhania and Paula Soto and Terry, {Valeri H} and Eric Verdin and Christopher Woelk and Stacey Wooden and Sifei Xing and Vicente Planelles",
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Spina, CA, Anderson, J, Archin, NM, Bosque, A, Chan, J, Famiglietti, M, Green, W, Kashuba, A, Lewin, SR, Margolis, DM, Mau, M, Ruelas, D, Saleh, S, Shirakawa, K, Siliciano, RF, Singhania, A, Soto, P, Terry, VH, Verdin, E, Woelk, C, Wooden, S, Xing, S & Planelles, V 2013, 'An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients', PLoS Pathogens, vol. 9, no. 12, e1003834. https://doi.org/10.1371/journal.ppat.1003834

An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. / Spina, Celsa A; Anderson, Jenny; Archin, Nancie M; Bosque, Alberto; Chan, Jonathan; Famiglietti, Marylinda; Green, Warner; Kashuba, Angela; Lewin, Sharon R; Margolis, David M; Mau, Matthew; Ruelas, Debbie; Saleh, Suha; Shirakawa, Kotaro; Siliciano, Robert F; Singhania, Akul; Soto, Paula; Terry, Valeri H; Verdin, Eric; Woelk, Christopher; Wooden, Stacey; Xing, Sifei; Planelles, Vicente.

In: PLoS Pathogens, Vol. 9, No. 12, e1003834, 2013.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients

AU - Spina, Celsa A

AU - Anderson, Jenny

AU - Archin, Nancie M

AU - Bosque, Alberto

AU - Chan, Jonathan

AU - Famiglietti, Marylinda

AU - Green, Warner

AU - Kashuba, Angela

AU - Lewin, Sharon R

AU - Margolis, David M

AU - Mau, Matthew

AU - Ruelas, Debbie

AU - Saleh, Suha

AU - Shirakawa, Kotaro

AU - Siliciano, Robert F

AU - Singhania, Akul

AU - Soto, Paula

AU - Terry, Valeri H

AU - Verdin, Eric

AU - Woelk, Christopher

AU - Wooden, Stacey

AU - Xing, Sifei

AU - Planelles, Vicente

PY - 2013

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N2 - The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for ?anti-latency? therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.

AB - The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for ?anti-latency? therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.

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