- Study aims to test mTOR inhibitors which reduce viral replication
in the gut T-cells which serve as viral reservoirs, thus improving the
chances of virus eradication.
Supplementing standard ART with mTOR inhibiting
treatments for HIV could offer better chances of cure
- Although current treatments are
effective in reducing viral load in the blood, the virus continues to
replicate in viral reservoirs in body tissues, particularly in the
gut, contributing to persistence of infection.
for the patient according to a recent study conducted
at the University of Montreal Hospital Research Centre
(CRCHUM). The results of the study appear in the September 2017 edition of the
journal JCI Insight.
ART alone may not be Sufficient in HIV Infection
(ART) for HIV has been
shown to be very effective in reducing viral load in the bloodstream, the virus
persists and multiplies in cells such as CD4+ T-cells
in other tissues.
Such cells that continue to harbor the virus are
termed "viral reservoirs"
"In spite of the effectiveness of
antivirals, it hides in specific immune system cells, the CD4 T cells, which
harbour the virus and form viral 'reservoirs' in various peripheral tissues,
particularly in the gastrointestinal tract," Ancula explained. "Inside
these 'reservoirs,' some viral organisms continue to replicate, which leads to
harmful inflammation in the gut. Hence the idea to limit viral replication at
all levels and to counteract inflammation.
‘Benefits cut from healthcare interventions and their complex needs could explain why people with schizophrenia are at an alarmingly higher risk of dying early.’
team hoped that targeting one such viral reservoir in the gut namely the CD4+
T-lymphocyte would aid in eradicating the virus
happens when T-Cells Migrate from the Bloodstream to the Gut
T-cells in the blood are directed to
migrate to the gut by the expression of certain
on their surface, for example, CCR6
(CD196), which act as a sort of HIV postal code. While migrating to the gut,
they acquire certain characteristics that render them vulnerable to HIV infection
"The digestive tract is an
environment conducive to viral 'reservoirs'," added the study's lead
author, Delphine Planas, a CRCHUM doctoral candidate. "Our research
demonstrates that CD4 T cells which migrate from the blood to the gut will be
modified. En route, they acquire the tools that aid the virus in infecting
them. Identifying these tools helps us understand why the gut represents a sort
of sanctuary favourable to HIV, and thus how to combat these
Prior research has shown that T-cells expressing CCR6 antigen are
preferentially targeted by the virus in vitro
and that these cells are
'viral reservoirs' in patients receiving ART.
of the Mammalian Target of Rapamycin (mTOR) Molecule in T-Cell Infection
The current team, along with one led by
Jean-Pierre Routy of the Research Institute of the McGill University Health
Centre (RI-MUHC), further analyzed T-cells obtained from biopsies of the
sigmoid colon in patients on ART.
They found that gut T-cells expressing CCR6 molecule also contained large amounts of
another molecule, namely the mTOR
which has been found to regulate several
important metabolic activities.
"It is the mTOR molecule which is in
part responsible for the high vulnerability to HIV of the CD4 T lymphocytes
expressing CCR6 and residing in the gut," explained Planas.
In fact dysregulated mTOR activation may
contribute to nephropathy, development of HIV associated cancers and other
effects of mTOR Inhibitors on Viral Replication
In in vitro testing of T-cells,
scientists have shown that using mTOR
inhibitors significantly reduces viral replication
and viral load,
especially when supplemented with existing medications.
The results appear promising and could
open up newer treatment options for HIV infection, one that may improve long term
and quality of life for the patient and hopefully even a cure.
of the Study
- The findings of the study certainly
seem to suggest that mTOR inhibitors could become a potential treatment
along with ART in persons infected with HIV.
- mTOR inhibitors have been
successfully employed in the treatment of other diseases namely diabetes
- Further studies are necessary to
validate the role of mTOR inhibitors in HIV infected patients.
"In specifically targeting CD4 T
cells carrying the CCR6 molecule, which contains dormant
HIV, we think these medications will
decrease gastrointestinal inflammation of individuals on ART," Ancuna
said. "Over the long term, we hope that this type of treatment will reduce
even more the amount of virus persisting in gut reservoirs. Therefore, this is
an important strategy to cure HIV, and one that deserves to be tested."
- Delphine Planas, Yuwei Zhang, Patricia Monteiro, Jean-Philippe Goulet, Annie Gosselin, Nathalie Grandvaux, Thomas J. Hope, Ariberto Fassati, Jean-Pierre Routy, Petronela Ancuta. HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms. JCI Insight.(2017);2(15):e93230. doi:10.1172/jci.insight.93230.
- Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice - (https://www.ncbi.nlm.nih.gov/pubmed/21624501)
- mTOR as a multifunctional therapeutic target in HIV infection. - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522811/)