Ignite Creation Date:
2024-05-06 @ 3:46 PM
Last Modification Date:
2024-10-26 @ 1:56 PM
Study NCT ID:
NCT04741100
Status:
WITHDRAWN
Last Update Posted:
2021-02-05
First Post:
2021-02-02
Brief Title:
Evaluation of Innovative Combinatorial stratégies of Anti-latency and Anti-immune Activation Drugs Targeting HIV Reservoir
Sponsor:
Centre de Recherches et dEtude sur la Pathologie Tropicale et le Sida
Organization:
Centre de Recherches et dEtude sur la Pathologie Tropicale et le Sida
Study Overview
Official Title:
Evaluation of Innovative Combinatorial stratégies of Anti-latency and Anti-immune Activation Drugs Targeting HIV Reservoir
Status:
WITHDRAWN
Status Verified Date:
2021-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
No patients Enrolled
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ERAVIR
Brief Summary:
Several barriers prevent the remission of HIV infection low level viremia HIV latency in the genome of host infected immune cells and persistent immune activation Targeting immune activation and viral latency represent the two intimately intricate goals to be envisaged for purging the reservoir in the perspective of HIV cure There is an urgent to develop and to test drugs targeting HIV latency HIV residual replication and immune activation alone or in synergistic combinations
We propose in this study to test agents with a potential effect on HIV latency by combining classical agents and newly discovered agents
The Pitié-Salpêtrière virology group has identified some new diaminopiperidine based compounds that have some antilatency properties through an activation of transcription Compounds of this new class will be tested in combination with classical agents HDAC inhibitors HMT inhibitors inducers of P-TEFb release PKC agonists DNMT inhibitors and less toxic compounds from classical categories for which Carine Van Lint University of Brussels has obtained preliminary HIV reactivation data
All the experimentations will be conducted in J-Lat cells and in ex- vivo CD4 cells sampled in patients from the Pitié-Salpêtrière HIV cohort
We propose in this study to test agents with a potential effect on HIV latency by combining classical agents and newly discovered agents
The Pitié-Salpêtrière virology group has identified some new diaminopiperidine based compounds that have some antilatency properties through an activation of transcription Compounds of this new class will be tested in combination with classical agents HDAC inhibitors HMT inhibitors inducers of P-TEFb release PKC agonists DNMT inhibitors and less toxic compounds from classical categories for which Carine Van Lint University of Brussels has obtained preliminary HIV reactivation data
All the experimentations will be conducted in J-Lat cells and in ex- vivo CD4 cells sampled in patients from the Pitié-Salpêtrière HIV cohort
Detailed Description:
Despite its major benefits cART implies mandatory lifespan treatment toxicity high costs and the inability to restore full-health thus urging the need to find a cure strategy and to revisit our approach to HIV therapy
HIV eradication is currently not achievable with standard cART due to the persistence of HIV reservoir maintained through low-level viremia immune activation despite plasma viral suppression and HIV latency
The possibility to achieve HIV eradication has been limited at least in part by the existence of latently infected cellular reservoirs The major known cellular reservoir is established in quiescent memory CD4 T cells providing an extremely long-lived set of cells in which the virus can remain transcriptionally silen Reactivation of latent viruses followed by the killing of the infected cells has been proposed as a possible strategy shock and kill to purge the latent reservoir None of them have been currently really successful Innovative strategies to target HIV reservoir are needed In parallel to clinical interventions there is a need to screen in vitro and ex vivo the best anti-latency and anti-immune activation candidates thus defining the optimal strategy targeting the reservoir
Research on the control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells in vivo and the absence of known phenotypic markers to distinguish those cells from uninfected cells In this setting cell-line models of latency have been very useful due to their genetic and experimental tractability Major conceptual leaps have been facilitated by the use of latently infected T cell lines including the ability to conduct genetic screens On the other hand latently infected cell lines are limited by their cycling nature and inherent mutations in growth controls and the clonal nature of the virus integration sites Such transformed cell lines lack the ability to differentiate and naturally oscillate between phases of quiescence and active proliferation in response to biological signals Because of these limitations several laboratories have recently developed primary cellular models of HIV-1 latency that capitalize on specific aspects of the T cell reservoir found in vivo These newer models allow easily and rapidly to study proposed virological and cellular mechanisms of latency and to evaluate novel small molecule compounds for induction of viral reactivation
One particular complex issue is the diversity of latency models and the many differences among them Disparities relate to the T-cell subsets represented the cellular signaling pathways capable of driving viral reactivation and the genetic composition of the viruses employed ranging from wild-type to functional deletion of multiple genes Additional differences reside in the experimental approaches taken to establish latent infection in these primary cell models which involve either infection of activated cycling cells later allowed to return to a resting state or direct infection of quiescent cells Because of such system variables screening efforts in specific cell models with identified drug candidates for anti-latency therapy often fail to reactivate HIV uniformly across the different models Therefore the activity of a drug candidate varies from one cellular model to another one or in cells from infected patients tested ex-vivo The current situation in this research field represents a critical knowledge gap that is adversely affecting our ability to identify promising treatment compounds and their associated molecular mechanisms and is hindering the advancement of drug testing into relevant animal models and ultimately human clinical trials
In a recent study induction of viral reactivation across several cell models was assessed using a selected common panel of stimuli known to function by distinct and defined mechanisms of action The panel included 13 treatments that modulate T cell processes such as T-cell receptor engagement protein kinase C PKC activation calcium influx cytokine signaling histone deacetylation and release of P-TEFb from the HEXIM7SK RNP complex This last study was designed to answer the following questions 1 are certain models of latency biased towards or against particular cell signaling pathways 2 can stimuli that work uniformly in multiple models be identified 3 can a central uniting theme or a single signaling pathway be responsible for control of viral latency and 4 can a model or limited group of models predict experimental drug activity in authentic latently infected cells from patients The results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients Most cell models demonstrated that sensitivity to HIV reactivation was skewed towards or against specific drug classes Protein kinase C agonists and PHA reactivated latent HIV uniformly across models although in most other drug classes did not
From these observations it is obvious that single agents will not be enough potent to induce an efficient stimulation of HIV transcription and latency disruption
We propose in the Eravir study to test several agents in combinations including classical agents and new classes of agents recently discovered in our institutions in their capacity to reactivate HIV
All experimentations will be conducted in J-Lat cells and in ex vivo CD4 cells sampled in HIV patients with a fully suppressed viremia on antiretroviral treatment
The team of Pitié-Salpêtrière has identified some new compounds diaminopiperidine based that have some properties that could disturb latency of HIV allowing an activation of transcription Compounds of this family will be tested in combination with classical agents such as HDAC inhibitors HMT inhibitors inducers of P-TEFb release PKC agonists DNMT inhibitors and also with compounds from these categories but less toxic for which Carine Van Lints lab University of Brussels has obtained preliminary HIV reactivation data
All the tests will be conducted in J-Lat cells and in ex vivo CD4 cells sampled in patients of Pitié-salpêtrière Hospital Paris and of Saint-Pierre Hospital Bruxells
Also frozen viable PBMC-samples will be dispatched from Belgium and France to the Spanish partner in order to test immune-activation and inflammation parameters
The research question will evaluate whether these above mentioned combination are capable to reactivate HIV from cellular models and ex vivo in patient cells
HIV eradication is currently not achievable with standard cART due to the persistence of HIV reservoir maintained through low-level viremia immune activation despite plasma viral suppression and HIV latency
The possibility to achieve HIV eradication has been limited at least in part by the existence of latently infected cellular reservoirs The major known cellular reservoir is established in quiescent memory CD4 T cells providing an extremely long-lived set of cells in which the virus can remain transcriptionally silen Reactivation of latent viruses followed by the killing of the infected cells has been proposed as a possible strategy shock and kill to purge the latent reservoir None of them have been currently really successful Innovative strategies to target HIV reservoir are needed In parallel to clinical interventions there is a need to screen in vitro and ex vivo the best anti-latency and anti-immune activation candidates thus defining the optimal strategy targeting the reservoir
Research on the control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells in vivo and the absence of known phenotypic markers to distinguish those cells from uninfected cells In this setting cell-line models of latency have been very useful due to their genetic and experimental tractability Major conceptual leaps have been facilitated by the use of latently infected T cell lines including the ability to conduct genetic screens On the other hand latently infected cell lines are limited by their cycling nature and inherent mutations in growth controls and the clonal nature of the virus integration sites Such transformed cell lines lack the ability to differentiate and naturally oscillate between phases of quiescence and active proliferation in response to biological signals Because of these limitations several laboratories have recently developed primary cellular models of HIV-1 latency that capitalize on specific aspects of the T cell reservoir found in vivo These newer models allow easily and rapidly to study proposed virological and cellular mechanisms of latency and to evaluate novel small molecule compounds for induction of viral reactivation
One particular complex issue is the diversity of latency models and the many differences among them Disparities relate to the T-cell subsets represented the cellular signaling pathways capable of driving viral reactivation and the genetic composition of the viruses employed ranging from wild-type to functional deletion of multiple genes Additional differences reside in the experimental approaches taken to establish latent infection in these primary cell models which involve either infection of activated cycling cells later allowed to return to a resting state or direct infection of quiescent cells Because of such system variables screening efforts in specific cell models with identified drug candidates for anti-latency therapy often fail to reactivate HIV uniformly across the different models Therefore the activity of a drug candidate varies from one cellular model to another one or in cells from infected patients tested ex-vivo The current situation in this research field represents a critical knowledge gap that is adversely affecting our ability to identify promising treatment compounds and their associated molecular mechanisms and is hindering the advancement of drug testing into relevant animal models and ultimately human clinical trials
In a recent study induction of viral reactivation across several cell models was assessed using a selected common panel of stimuli known to function by distinct and defined mechanisms of action The panel included 13 treatments that modulate T cell processes such as T-cell receptor engagement protein kinase C PKC activation calcium influx cytokine signaling histone deacetylation and release of P-TEFb from the HEXIM7SK RNP complex This last study was designed to answer the following questions 1 are certain models of latency biased towards or against particular cell signaling pathways 2 can stimuli that work uniformly in multiple models be identified 3 can a central uniting theme or a single signaling pathway be responsible for control of viral latency and 4 can a model or limited group of models predict experimental drug activity in authentic latently infected cells from patients The results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients Most cell models demonstrated that sensitivity to HIV reactivation was skewed towards or against specific drug classes Protein kinase C agonists and PHA reactivated latent HIV uniformly across models although in most other drug classes did not
From these observations it is obvious that single agents will not be enough potent to induce an efficient stimulation of HIV transcription and latency disruption
We propose in the Eravir study to test several agents in combinations including classical agents and new classes of agents recently discovered in our institutions in their capacity to reactivate HIV
All experimentations will be conducted in J-Lat cells and in ex vivo CD4 cells sampled in HIV patients with a fully suppressed viremia on antiretroviral treatment
The team of Pitié-Salpêtrière has identified some new compounds diaminopiperidine based that have some properties that could disturb latency of HIV allowing an activation of transcription Compounds of this family will be tested in combination with classical agents such as HDAC inhibitors HMT inhibitors inducers of P-TEFb release PKC agonists DNMT inhibitors and also with compounds from these categories but less toxic for which Carine Van Lints lab University of Brussels has obtained preliminary HIV reactivation data
All the tests will be conducted in J-Lat cells and in ex vivo CD4 cells sampled in patients of Pitié-salpêtrière Hospital Paris and of Saint-Pierre Hospital Bruxells
Also frozen viable PBMC-samples will be dispatched from Belgium and France to the Spanish partner in order to test immune-activation and inflammation parameters
The research question will evaluate whether these above mentioned combination are capable to reactivate HIV from cellular models and ex vivo in patient cells
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None