HIV-AIDS Infection – Novel Therapy Reduces Viral Replication In The Gut

Highlights:

• 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.

• 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.

Supplementing standard ART with mTOR inhibiting treatments for HIV could offer better chances of cure 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.

Why ART alone may not be Sufficient in HIV Infection

Although anti-retroviral therapy (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.

The research team hoped that targeting one such viral reservoir in the gut namely the CD4+ T-lymphocyte would aid in eradicating the virus completely.

What happens when T-Cells Migrate from the Bloodstream to the Gut

 Some T-cells in the blood are directed to migrate to the gut by the expression of certain

antigens 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 'reservoirs'."

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.

Role 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 complications.

Testing 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 survival, and quality of life for the patient and hopefully even a cure.

Scope 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 and cancer.

• 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."

Reference:

1. 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.
2. 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)
3. mTOR as a multifunctional therapeutic target in HIV infection. - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522811/)

Source-Medindia