title: The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function.
abstract: Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.
authors.affiliation: Department of Microbiology &Immunology, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: G
authors.initials: G
authors.lastname: Clutton
authors.affiliation: Department of Microbiology &Immunology, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biostatistics, UNC Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Baldoni
authors.affiliation: Lineberger Comprehensive Care Center, UNC Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Mollan
authors.affiliation: Department of Medicine and UNC HIV Cure Center, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kirchherr
authors.affiliation: Merck Research Laboratories, White Horse Junction, Pennsylvania, USA.
authors.forename: W
authors.initials: W
authors.lastname: Newhard
authors.affiliation: Merck Research Laboratories, White Horse Junction, Pennsylvania, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Cox
authors.affiliation: Department of Medicine and UNC HIV Cure Center, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Kuruc
authors.affiliation: Eshelman School of Pharmacy, UNC Chapel Hill, North Carolina, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kashuba
authors.affiliation: Merck Research Laboratories, White Horse Junction, Pennsylvania, USA.
authors.forename: R
authors.initials: R
authors.lastname: Barnard
authors.affiliation: Department of Medicine and UNC HIV Cure Center, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: N
authors.initials: N
authors.lastname: Archin
authors.affiliation: Department of Medicine and UNC HIV Cure Center, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Gay
authors.affiliation: Department of Biostatistics, UNC Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Department of Microbiology &Immunology, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Department of Medicine and UNC HIV Cure Center, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Margolis
authors.affiliation: Department of Microbiology &Immunology, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Department of Medicine and UNC HIV Cure Center, UNC Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: N
authors.initials: N
authors.lastname: Goonetilleke
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D017735:Virus Latency / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D047428:Protein Kinase Inhibitors; D000077337:Vorinostat; D000077767:Panobinostat