title: Elimination of HIV-1-Infected Primary T Cell Reservoirs in an In Vitro Model of Latency.
abstract: Establishment of long-lived cellular reservoirs of HIV-1 represents a major therapeutic challenge to virus eradication. In this study, we utilized a human primary cell model of HIV-1 latency to evaluate the requirements for efficient virus reactivation from, and the selective elimination of, latently infected human T cells. Ectopic expression of BCL2 supported the replication and spread of R5-tropic HIV-1 in activated CD4(+) T cells. After IL-2 withdrawal, the HIV-1-infected T cells survived as resting cells for several months. Unexpectedly, these resting T cells continue to produce detectable levels of infectious virus, albeit at a lower frequency than cells maintained in IL-2. In the presence of HIV-1 inhibitors, reactivation of the resting T cells with γc-cytokines and allogeneic dendritic cells completely extinguished HIV-1 infectivity. We also evaluated the ability of the bacterial LukED cytotoxin to target and kill CCR5-expressing cells. After γc-cytokine stimulation, LukED treatment eliminated both HIV-1-infected resting cells and the non-infected CCR5+ cells. Importantly, complete clearance of in vitro HIV-1 reservoirs by LukED required a lower threshold of cytokine signals relative to HIV-1 inhibitors. Thus, the primary T cell-based HIV-1 latency model could facilitate the development of novel agents and therapeutic strategies that could effectively eradicate HIV-1.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Rawlings
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Francis
authors.initials: F
authors.lastname: Alonzo
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Torres
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America; Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D004197:Disease Reservoirs; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D017735:Virus Latency; D014779:Virus Replication