Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat.
Details
Serval ID
serval:BIB_88943194E009
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat.
Journal
Journal of virology
ISSN
1098-5514 (Electronic)
ISSN-L
0022-538X
Publication state
Published
Issued date
10/2015
Peer-reviewed
Oui
Volume
89
Number
20
Pages
10176-10189
Language
english
Notes
Publication types: Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
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.
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/genetics, Antigens, CD/immunology, Antiretroviral Therapy, Highly Active, CD4-Positive T-Lymphocytes/drug effects, CD4-Positive T-Lymphocytes/enzymology, CD4-Positive T-Lymphocytes/immunology, CD4-Positive T-Lymphocytes/virology, CD8-Positive T-Lymphocytes/drug effects, CD8-Positive T-Lymphocytes/enzymology, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/virology, Cell Count, DNA, Viral/antagonists & inhibitors, DNA, Viral/genetics, DNA, Viral/immunology, Dendritic Cells/drug effects, Dendritic Cells/enzymology, Dendritic Cells/immunology, Dendritic Cells/virology, Drug Administration Schedule, Gene Expression, Genotype, HIV Infections/drug therapy, HIV Infections/enzymology, HIV Infections/immunology, HIV Infections/virology, HIV-1/drug effects, HIV-1/growth & development, HIV-1/immunology, Histone Deacetylase Inhibitors/therapeutic use, Histone Deacetylases/genetics, Histone Deacetylases/immunology, Humans, Hydroxamic Acids/therapeutic use, Immunity, Innate/drug effects, Indoles/therapeutic use, Interferons, Interleukins/genetics, Interleukins/immunology, Killer Cells, Natural/drug effects, Killer Cells, Natural/enzymology, Killer Cells, Natural/immunology, Killer Cells, Natural/virology, Panobinostat, Virus Latency/drug effects
Pubmed
Web of science
Open Access
Yes
Create date
17/08/2016 10:28
Last modification date
09/04/2024 6:14