title: Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat.
abstract: The pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3(-) CD56(+) total NK cells and CD16(+) CD56(dim) NK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69(+) NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of the IL28B CC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies.
  
  
  OBJECTIVE
  Currently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the "shock-and-kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells.
authors.affiliation: Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Olesen
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Selena
authors.initials: S
authors.lastname: Vigano
authors.affiliation: Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Ouyang
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Buzon
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Arman
authors.initials: A
authors.lastname: Bashirova
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
authors.affiliation: Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christel R
authors.initials: CR
authors.lastname: Brinkmann
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.affiliation: Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts, USA Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA mlichterfeld@mgh.harvard.edu.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology; D002452:Cell Count; D004279:DNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology; D004334:Drug Administration Schedule; D015870:Gene Expression; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007113:Immunity, Innate / Q000187:drug effects*; D007211:Indoles / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology; D000077767:Panobinostat; D017735:Virus Latency / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D015703:Antigens, CD; D004279:DNA, Viral; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007211:Indoles; D007372:Interferons; D007378:Interleukins; D000077767:Panobinostat; C000624353:interferon-lambda, human; D000095022:Interferon Lambda