Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Rikke Olesen; Selena Vigano; Thomas A Rasmussen; Ole S Søgaard; Zhengyu Ouyang; Maria Buzon; Arman Bashirova; Mary Carrington; Sarah Palmer; Christel R Brinkmann; Xu G Yu; Lars Jørgen Østergaard; Martin Tolstrup; Mathias Lichterfeld

doi:10.1128/JVI.01484-15

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Rikke Olesen
, Selena Vigano
, Thomas A Rasmussen
, Ole S Søgaard
, Zhengyu Ouyang
, Maria Buzon
, Arman Bashirova
, Mary Carrington
, Sarah Palmer
, Christel R Brinkmann
, Xu G Yu
, Lars Jørgen Østergaard
, Martin Tolstrup
, Mathias Lichterfeld

Department of Clinical Medicine - Department of Infectious Diseases

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

77 Citations (Scopus)

Abstract

UNLABELLED: 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.

IMPORTANCE: 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.

Original language	English
Journal	Journal of Virology
Volume	89
Issue	20
Pages (from-to)	10176-89
Number of pages	14
ISSN	0022-538X
DOIs	https://doi.org/10.1128/JVI.01484-15
Publication status	Published - Oct 2015

Keywords

Antigens, CD
Antiretroviral Therapy, Highly Active
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Count
DNA, Viral
Dendritic Cells
Drug Administration Schedule
Gene Expression
Genotype
HIV Infections
HIV-1
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Hydroxamic Acids
Immunity, Innate
Indoles
Interleukins
Killer Cells, Natural
Virus Latency

Access to Document

10.1128/JVI.01484-15

Library access?

Check availability with the Royal Danish Library

Cite this

Olesen, R., Vigano, S., Rasmussen, T. A., Søgaard, O. S., Ouyang, Z., Buzon, M., Bashirova, A., Carrington, M., Palmer, S., Brinkmann, C. R., Yu, X. G., Østergaard, L. J., Tolstrup, M., & Lichterfeld, M. (2015). Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat. Journal of Virology, 89(20), 10176-89. https://doi.org/10.1128/JVI.01484-15

@article{6d0593263c054a5ba3e2b69d7ac305ec,

title = "Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat",

abstract = "UNLABELLED: 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.IMPORTANCE: 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.",

keywords = "Antigens, CD, Antiretroviral Therapy, Highly Active, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Count, DNA, Viral, Dendritic Cells, Drug Administration Schedule, Gene Expression, Genotype, HIV Infections, HIV-1, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Immunity, Innate, Indoles, Interleukins, Killer Cells, Natural, Virus Latency",

author = "Rikke Olesen and Selena Vigano and Rasmussen, \{Thomas A\} and S{\o}gaard, \{Ole S\} and Zhengyu Ouyang and Maria Buzon and Arman Bashirova and Mary Carrington and Sarah Palmer and Brinkmann, \{Christel R\} and Yu, \{Xu G\} and {\O}stergaard, \{Lars J{\o}rgen\} and Martin Tolstrup and Mathias Lichterfeld",

year = "2015",

month = oct,

doi = "10.1128/JVI.01484-15",

language = "English",

volume = "89",

pages = "10176--89",

journal = "Journal of Virology",

issn = "0022-538X",

publisher = "American Society for Microbiology",

number = "20",

}

Olesen, R, Vigano, S, Rasmussen, TA , Søgaard, OS, Ouyang, Z, Buzon, M, Bashirova, A, Carrington, M, Palmer, S, Brinkmann, CR, Yu, XG, Østergaard, LJ , Tolstrup, M & Lichterfeld, M 2015, 'Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat', Journal of Virology, vol. 89, no. 20, pp. 10176-89. https://doi.org/10.1128/JVI.01484-15

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat. / Olesen, Rikke; Vigano, Selena; Rasmussen, Thomas A et al.
In: Journal of Virology, Vol. 89, No. 20, 10.2015, p. 10176-89.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

AU - Olesen, Rikke

AU - Vigano, Selena

AU - Rasmussen, Thomas A

AU - Søgaard, Ole S

AU - Ouyang, Zhengyu

AU - Buzon, Maria

AU - Bashirova, Arman

AU - Carrington, Mary

AU - Palmer, Sarah

AU - Brinkmann, Christel R

AU - Yu, Xu G

AU - Østergaard, Lars Jørgen

AU - Tolstrup, Martin

AU - Lichterfeld, Mathias

PY - 2015/10

Y1 - 2015/10

N2 - UNLABELLED: 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.IMPORTANCE: 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.

AB - UNLABELLED: 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.IMPORTANCE: 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.

KW - Antigens, CD

KW - Antiretroviral Therapy, Highly Active

KW - CD4-Positive T-Lymphocytes

KW - CD8-Positive T-Lymphocytes

KW - Cell Count

KW - DNA, Viral

KW - Dendritic Cells

KW - Drug Administration Schedule

KW - Gene Expression

KW - Genotype

KW - HIV Infections

KW - HIV-1

KW - Histone Deacetylase Inhibitors

KW - Histone Deacetylases

KW - Humans

KW - Hydroxamic Acids

KW - Immunity, Innate

KW - Indoles

KW - Interleukins

KW - Killer Cells, Natural

KW - Virus Latency

U2 - 10.1128/JVI.01484-15

DO - 10.1128/JVI.01484-15

M3 - Journal article

C2 - 26223643

SN - 0022-538X

VL - 89

SP - 10176

EP - 10189

JO - Journal of Virology

JF - Journal of Virology

IS - 20

ER -

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Abstract

Keywords

Access to Document

Library access?

Fingerprint

Cite this