title: In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection.
abstract: The latent reservoir in resting CD4(+) T cells presents a major barrier to HIV cure. Latency-reversing agents are therefore being developed with the ultimate goal of disrupting the latent state, resulting in induction of HIV expression and clearance of infected cells. Histone deacetylase inhibitors (HDACi) have received a significant amount of attention for their potential as latency-reversing agents.
  
  
  
  Here, we have investigated the in vitro and systemic in vivo effect of panobinostat, a clinically relevant HDACi, on HIV latency. We showed that panobinostat induces histone acetylation in human PBMCs. Further, we showed that panobinostat induced HIV RNA expression and allowed the outgrowth of replication-competent virus ex vivo from resting CD4(+) T cells of HIV-infected patients on suppressive antiretroviral therapy (ART). Next, we demonstrated that panobinostat induced systemic histone acetylation in vivo in the tissues of BLT humanized mice. Finally, in HIV-infected, ART-suppressed BLT mice, we evaluated the effect of panobinostat on systemic cell-associated HIV RNA and DNA levels and the total frequency of latently infected resting CD4(+) T cells. Our data indicate that panobinostat treatment resulted in systemic increases in cellular levels of histone acetylation, a key biomarker for in vivo activity. However, panobinostat did not affect the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells.
  
  
  
  We have demonstrated robust levels of systemic histone acetylation after panobinostat treatment of BLT humanized mice; and we did not observe a detectable change in the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells in HIV-infected, ART-suppressed BLT mice. These results are consistent with the modest effects noted in vitro and suggest that combination therapies may be necessary to reverse latency and enable clearance. Animal models will contribute to the progress towards an HIV cure.
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA.
authors.forename: Perry
authors.initials: P
authors.lastname: Tsai
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Baker
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA.
authors.forename: William O
authors.initials: WO
authors.lastname: Thayer
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA.
authors.forename: Rae Ann
authors.initials: RA
authors.lastname: Spagnuolo
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Sanchez
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barrett
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Howell
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA.
authors.forename: David
authors.initials: D
authors.lastname: Margolis
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA. nancie_archin@med.unc.edu.
authors.forename: Nancie M
authors.initials: NM
authors.lastname: Archin
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Rd., CB 7042, Genetic Medicine Building 2043, Chapel Hill, NC, 27599, USA. victor_garcia@med.unc.edu.
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000107:Acetylation; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D004279:DNA, Viral / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000077767:Panobinostat; D012367:RNA, Viral / Q000097:blood / Q000378:metabolism*; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D012367:RNA, Viral; D000077767:Panobinostat
keywords: BLT; HIV; Histone acetylation; Humanized mice; Latency; Panobinostat