New drug target against HIV permissiveness in CD4+ T cells

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Researchers from the University of Montreal Hospital Research Centre (CRCHUM, Quebec, Canada) have discovered a method to reduce viral replication in gut CD4+ T cells that contribute to HIV-1 persistence during antiretroviral therapy (ART).

Currently available ART restores CD4 counts and efficiently controls viral replication, often reducing viral loads to an undetectable blood level; however, total HIV eradication is yet to be achieved.

“In spite of the effectiveness of ART, [HIV] 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,” explained author Petronela Ancuta of CRCHUM. “Inside these ‘reservoirs,’ some viral particles 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 recent findings, published last month in JCI Insight, demonstrate promise for a novel therapeutic strategy that could supplement ART and prevent complications associated with chronic infection.

“We have identified a molecule that stimulates HIV replication in CD4 T cells located in the gut,” stated Ancuta. “We have also started testing medications to block this replication and decrease inflammation of the intestinal mucosa. This is a promising new approach to eradicate HIV, or at least to achieve a functional cure.”

CD4+ T cells can migrate from the blood to the gastrointestinal tract  due to their cell-surface molecules. The homing of CD4 T cells into the gut is has previously been reported to be mediated by CCR6, which acts as a marker for these cells to become HIV targets, and promote persistence.

After studying the blood and biopsies of the sigmoid colon from HIV-infected individuals on ART therapy, researchers at CRCHUM discovered that CCR6+ T cells overexpressed an important regulator of cellular growth; mTOR.

“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,” described the study’s lead author, Delphine Planas, a doctoral candidate of CRCHUM.

Using mTOR inhibitors to investigate this pathway further, researchers reduced the activity of the mTOR pathway in vitro and slowed HIV replication in cells of 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,” Ancuta declared. “Over the long term, we hope that this type of treatment will reduce the amount of virus persisting in gut reservoirs. Therefore, this is an important strategy to cure HIV, and one that deserves to be tested.”

Sources: Planas D,  Zhang Y, Monteiro P et al. HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms. JCI insight. 10.1172/jci.insight.93230 (2017); http://crchum.chumontreal.qc.ca/en/news-briefs/hiv-aids-following-your-gut

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