Epigenetic drug Gar1041 in combination with antiretroviral therapy (ART) transiently reduces the pro...
Download
1 / 18

Andrea Savarino - PowerPoint PPT Presentation


  • 97 Views
  • Uploaded on

Epigenetic drug Gar1041 in combination with antiretroviral therapy (ART) transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques. Andrea Savarino. Objectives.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Andrea Savarino' - jerom


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

Epigenetic drug Gar1041 in combination with antiretroviral therapy (ART) transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques

Andrea Savarino


Objectives
Objectives therapy (ART) transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques

  • To develop an antiretroviral treatment regimen in SIV infected macaques that could be used to test eradication strategies

  • To increase the numbers and classes of effective antiviral drug for use in macaques that mirror treatments in human HIV cases

  • To initiate preliminary studies to determine if virus eradication or disease alteration is possible


Virus reservoirs eradication
Virus Reservoirs Eradication therapy (ART) transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques

  • Prevent any virus spread by intensified ART

    • Target multiple sites of viral inhibition

  • Induce latently infected cells to replicate virus

    • Histone deacetylase inhibitors

  • Eliminate productive/infected cells

    • Virus replication/cytotoxicity

    • Immune response

    • Passive therapies


Stimulation of HIV-1 LTR-controlled expression of GFP by MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1).

Savarino, et al., Retrovirology 2009.


NF- MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1)kB nuclear translocation

Reactive oxygen species (ROS)

induction

Gar1041 72 h

Gar1041 12 h

Gar 1041 3 h

TNF-a 72 h

Pos. control (TNF-a 1.5 h)

ACH2 ctrl

0.6 μM GAR1041

p24 induction

Gar1041

Gar1041

Gar1041


CD27 Downregulation MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1)

TN

TCM

TTM

TEM

Mock

50nM Gar1041


Response of SIVmac251-infected macaques to raltegravir MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1)

RAL +

PMPA + FTC

RAL

RAL + PMPA + FTC

RAL

RAL- 100mg BID, oral

PMPA - 20mg/kg, SQ

FTC – 50mg/kg, SQ

Lewis M. Norelli S., et al., Retrovirology 2010.


Treatment of monkeys with ART plus Gar1041 MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1)

P < 0.05

*P < 0.05

**P < 0.01

***P < 0.001

P < 0.05


Darunavir (DRV) complexed with HIV-2 protease MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1)

DRV complexed with SIVmac251 protease

Kovalevsky et al.,

2008

Barreca ML, Norelli S, and Savarino A,

unpublished



Proviral DNA in PBMC from SIV+ Macaques Following Addition of Ritonavir-boosted Darunavir ART/Gar1041 Regimen.

iART/Gar1041 (average trend over time: P = 0.0207; t-test for regression).

iART alone (average trend over time: P = 0.8878; t-test for regression).


Stimulation of viral replication by histone deacetylase inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041

*P < 0.05

**P < 0.01

iART alone

iART plus Gar1041


Re-appearance of viral loads following treatment suspension inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041

Intensified ART alone

Intensified ART plus Gar1041

*

3 SAHA cycles

2 SAHA cycles

*

*P < 0.05; Gehan-Breslow-Wilcoxon test for survival


Drug free remission… eventually? inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041

iART plus Gar1041

iART alone

*P < 0.05; paired Student’s t-test


Drug free remission… eventually? inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041

iART alone

iART plus Gar1041


Conclusions
Conclusions inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041

Preliminary studies using oxidative stress inducing agents indicate the utility of the simian model to assess in-vivo the effectiveness of treatments that may stimulate the removal of latently infected cells

Our findings suggest that Gar1041 impacts the proviral DNA reservoir in SIVmac251-infected macaques under treatment with ART, likely acting by an entirely novel mechanism (differentiation of long-lived or proliferation-competent memory T cells into short-lived effector-like phenotypes).

They also highlight the need for ART intensification when adopting drugs capable of inducing HIV-1 replication.


Acknowledgments
Acknowledgments inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041

Bioqual

Matt Collins

Jake Yalley-Ogunro University of Rome “Tor Vergata”

Jack Greenhouse Enrico Garaci

Wendy Wagner

ICGEB

Istituto Superiore di Sanità, RomeMarina Lusic

Sandro Norelli

Barbara Chirullo University of Rome, La Sapienza

Marco Sgarbanti Rossella Sgarbanti

Andrea Savarino Anna Teresa Palamara


ad