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Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sékaly RP, Lewin SR - PLoS Pathog. (2014)

Bottom Line: CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose.Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA.Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.

ABSTRACT

Unlabelled: Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.

Trial registration: ClinicalTrials.gov NCT01365065.

No MeSH data available.


Related in: MedlinePlus

Individual changes in CA-US HIV RNA in blood and tissue.A) Fold change in CA-US HIV RNA following vorinostat in CD4+ T-cells from blood (left panel) and rectal tissue (right panel) compared to baseline. The maximum fold change in CA-US HIV RNA on study (solid column) and change at day 84 (open column) is shown for CD4+ T-cells from blood; and change at day 14 for rectal tissue is shown for each participant (upper panel) and the median (IQR) change for all participants (lower panel). The grey dashed line indicates 1-fold change. B) Time to reach maximum fold increase in CA-US HIV RNA for each participant. Grey shaded box represents the time on vorinostat. (C) Correlation between baseline CA-US HIV RNA and peak CA-US HIV RNA (left panel) and day 84 CA-US HIV RNA (right panel).
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ppat-1004473-g002: Individual changes in CA-US HIV RNA in blood and tissue.A) Fold change in CA-US HIV RNA following vorinostat in CD4+ T-cells from blood (left panel) and rectal tissue (right panel) compared to baseline. The maximum fold change in CA-US HIV RNA on study (solid column) and change at day 84 (open column) is shown for CD4+ T-cells from blood; and change at day 14 for rectal tissue is shown for each participant (upper panel) and the median (IQR) change for all participants (lower panel). The grey dashed line indicates 1-fold change. B) Time to reach maximum fold increase in CA-US HIV RNA for each participant. Grey shaded box represents the time on vorinostat. (C) Correlation between baseline CA-US HIV RNA and peak CA-US HIV RNA (left panel) and day 84 CA-US HIV RNA (right panel).

Mentions: There was a significant increase in CA-US HIV RNA in CD4+ T-cells from blood between baseline and the primary endpoint at day 14 (p<0.001). Intra-individual change in CA-US HIV RNA from baseline was significant in 90% (18/20) of participants on at least one time point during vorinostat dosing. The median fold change in CA-US HIV RNA from baseline to peak in CD4+ T-cells from blood was 7.4 (IQR 3.4, 9.1) and in rectal tissue from baseline to day 14 was 1.4 (IQR 0.8, 2.8; Figure 2A; individual fold changes shown in Figure S2). The time to peak change in CA-US HIV RNA in blood varied from 8 hours to 84 days (Figure 2B). CA-US HIV RNA at peak and day 84 correlated with baseline values (p<0.0001 for both; ρ = 0.23 and 0.39 respectively; Figure 2C). The increase in CA-US RNA was statistically significant by 8 hours after first dose and remained elevated throughout follow-up, including throughout the 70 day period after vorinostat dosing (p<0.001 for all time points for both comparison of raw data in copies per million 18s or when measured by fold-change, except day 28; Figure 3A). Using a generalised estimating equation (GEE) analysis, the mean fold change in CA-US HIV RNA relative to baseline at time points during vorinostat was 2.65 (95% CI 1.76, 3.52, p = 0.023) and at time points after vorinostat (study days 21, 28 and 84) was 3.00 (95% CI 2.16, 3.84, p = 0.018). There was a trend toward an increase between baseline and day 14 in CA-US HIV RNA in CD3+ T-cells from rectal tissue (p = 0.08; Figure 3A). There was no statistically significant correlation between changes in CA-US HIV RNA and changes in acetylation of H3, lysine and H4 (p>0.05 for all comparisons).


Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sékaly RP, Lewin SR - PLoS Pathog. (2014)

Individual changes in CA-US HIV RNA in blood and tissue.A) Fold change in CA-US HIV RNA following vorinostat in CD4+ T-cells from blood (left panel) and rectal tissue (right panel) compared to baseline. The maximum fold change in CA-US HIV RNA on study (solid column) and change at day 84 (open column) is shown for CD4+ T-cells from blood; and change at day 14 for rectal tissue is shown for each participant (upper panel) and the median (IQR) change for all participants (lower panel). The grey dashed line indicates 1-fold change. B) Time to reach maximum fold increase in CA-US HIV RNA for each participant. Grey shaded box represents the time on vorinostat. (C) Correlation between baseline CA-US HIV RNA and peak CA-US HIV RNA (left panel) and day 84 CA-US HIV RNA (right panel).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231123&req=5

ppat-1004473-g002: Individual changes in CA-US HIV RNA in blood and tissue.A) Fold change in CA-US HIV RNA following vorinostat in CD4+ T-cells from blood (left panel) and rectal tissue (right panel) compared to baseline. The maximum fold change in CA-US HIV RNA on study (solid column) and change at day 84 (open column) is shown for CD4+ T-cells from blood; and change at day 14 for rectal tissue is shown for each participant (upper panel) and the median (IQR) change for all participants (lower panel). The grey dashed line indicates 1-fold change. B) Time to reach maximum fold increase in CA-US HIV RNA for each participant. Grey shaded box represents the time on vorinostat. (C) Correlation between baseline CA-US HIV RNA and peak CA-US HIV RNA (left panel) and day 84 CA-US HIV RNA (right panel).
Mentions: There was a significant increase in CA-US HIV RNA in CD4+ T-cells from blood between baseline and the primary endpoint at day 14 (p<0.001). Intra-individual change in CA-US HIV RNA from baseline was significant in 90% (18/20) of participants on at least one time point during vorinostat dosing. The median fold change in CA-US HIV RNA from baseline to peak in CD4+ T-cells from blood was 7.4 (IQR 3.4, 9.1) and in rectal tissue from baseline to day 14 was 1.4 (IQR 0.8, 2.8; Figure 2A; individual fold changes shown in Figure S2). The time to peak change in CA-US HIV RNA in blood varied from 8 hours to 84 days (Figure 2B). CA-US HIV RNA at peak and day 84 correlated with baseline values (p<0.0001 for both; ρ = 0.23 and 0.39 respectively; Figure 2C). The increase in CA-US RNA was statistically significant by 8 hours after first dose and remained elevated throughout follow-up, including throughout the 70 day period after vorinostat dosing (p<0.001 for all time points for both comparison of raw data in copies per million 18s or when measured by fold-change, except day 28; Figure 3A). Using a generalised estimating equation (GEE) analysis, the mean fold change in CA-US HIV RNA relative to baseline at time points during vorinostat was 2.65 (95% CI 1.76, 3.52, p = 0.023) and at time points after vorinostat (study days 21, 28 and 84) was 3.00 (95% CI 2.16, 3.84, p = 0.018). There was a trend toward an increase between baseline and day 14 in CA-US HIV RNA in CD3+ T-cells from rectal tissue (p = 0.08; Figure 3A). There was no statistically significant correlation between changes in CA-US HIV RNA and changes in acetylation of H3, lysine and H4 (p>0.05 for all comparisons).

Bottom Line: CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose.Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA.Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Victoria, Australia; Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.

ABSTRACT

Unlabelled: Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.

Trial registration: ClinicalTrials.gov NCT01365065.

No MeSH data available.


Related in: MedlinePlus