Journal Article

An In-Depth Comparison of Latent HIV-1 Reactivation in Multiple Cell Model Systems and Resting CD4+ T Cells from Aviremic Patients

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

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetamides - pharmacology / Acquired immune deficiency syndrome / Adult / AIDS / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - virology / Cell research / Cells, Cultured / Health aspects / HEK293 Cells / Histone Deacetylase Inhibitors - pharmacology / HIV (Viruses) / HIV Infections - immunology / HIV Infections - pathology / HIV Infections - virology / HIV-1 - drug effects / HIV-1 - physiology / Host-parasite relationships / Humans / Hydroxamic Acids - pharmacology / Interleukin-7 - pharmacology / Jurkat Cells / Kinases / Lymphocytes / Medical research / Models, Biological / Patients / Physiological aspects / Studies / T cells / Veterans / Virus Activation - drug effects / Virus Latency - drug effects / Vorinostat