Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04741100 |
| Other study ID # |
CREPATS 04 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 15, 2020 |
| Est. completion date |
December 15, 2020 |
Study information
| Verified date |
February 2021 |
| Source |
Centre de Recherches et d'Etude sur la Pathologie Tropicale et le Sida |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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.
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 HEXIM/7SK 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
Lint's 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.
