title: An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients.
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.
authors.affiliation: Veterans Administration San Diego Healthcare System, San Diego, California, United States of America ; Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Celsa A
authors.initials: CA
authors.lastname: Spina
authors.affiliation: Department of Infectious Diseases, Alfred Hospital, Melbourne, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Nancie M
authors.initials: NM
authors.lastname: Archin
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chan
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Marylinda
authors.initials: M
authors.lastname: Famiglietti
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America ; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Warner C
authors.initials: WC
authors.lastname: Greene
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Kashuba
authors.affiliation: Department of Infectious Diseases, Alfred Hospital, Melbourne, Australia ; Monash University, Melbourne, Australia ; Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mau
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Debbie
authors.initials: D
authors.lastname: Ruelas
authors.affiliation: Department of Infectious Diseases, Alfred Hospital, Melbourne, Australia.
authors.forename: Suha
authors.initials: S
authors.lastname: Saleh
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Howard Hughes Medical Institute, Baltimore, Maryland, United States of America.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
authors.affiliation: Veterans Administration San Diego Healthcare System, San Diego, California, United States of America.
authors.forename: Akul
authors.initials: A
authors.lastname: Singhania
authors.affiliation: Veterans Administration San Diego Healthcare System, San Diego, California, United States of America ; Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Paula C
authors.initials: PC
authors.lastname: Soto
authors.affiliation: Veterans Administration San Diego Healthcare System, San Diego, California, United States of America.
authors.forename: Valeri H
authors.initials: VH
authors.lastname: Terry
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America ; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Woelk
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Stacey
authors.initials: S
authors.lastname: Wooden
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Howard Hughes Medical Institute, Baltimore, Maryland, United States of America.
authors.forename: Sifei
authors.initials: S
authors.lastname: Xing
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D019169:Jurkat Cells; D008954:Models, Biological; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D000081:Acetamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015851:Interleukin-7; D000077337:Vorinostat; C014026:hexamethylene bisacetamide