An Antidiabetic Helps the Immune System Recognize Reservoirs of HIV

The AHA! Team — Wed, 25 Sep 2024 08:29:56 +0000

Universite de Montreal via Newswise – Metformin, a drug used to treat type 2 diabetes, could help deplete the viral reservoir and eliminate it entirely in people living with HIV who receive antiretroviral therapy, Canadian researchers say in a new study. In 2021, a team led by immunologist Petronela Ancuta of Université de Montréal’s affiliated hospital research centre, the CRCHUM, showed that metformin, when taken for three months, improved patients’ immunity and reduced the chronic inflammation usually associated with complications such as cardiovascular disease. One reason these benefits are so effective is that metformin inhibits the activity of the mTOR (mechanistic target of rapamycin) molecule, which in turn slows down HIV replication in the cells of patients infected with the virus. In the journal iScience, Ancuta and her student Augustine Fert, the study’s first author and a recent Ph.D. holder, go further. They studied the molecular mechanisms of action of metformin on HIV replication in CD4 T lymphocytes, which are immune system cells that provide shelter for the virus. In these reservoirs, HIV keeps on replicating, which contributes to the chronic inflammation by constantly activating the immune system. “The results of our in vitro tests on cells from people living with HIV and treated with antiretroviral therapy caught us off guard at first,” said Ancuta. “They were a bit surprising. We discovered that metformin had both a proviral and an antiviral effect. The drug helped boost the number of HIV-infected cells, while also stopping the virus from escaping the cell.” Antibodies to the rescue Another benefit of metformin is that it overexpresses the BST2 protein, which acts as a kind of glue to keep virions clinging to the surface of HIV-infected cells. The immune system then spots them and can target them with antibodies. “Together with my colleague Andrés Finzi, we tested the ability of several broad-spectrum neutralizing anti-HIV antibodies to recognize viral reservoir cells after metformin exposure in vitro,” said Ancuta. “Some of them recognized the virus very well, suggesting their ability to attract and trigger the destruction of infected cells by NK cells through a process of cellular cytotoxicity.” These recent scientific advances mean that the “shock-and-kill” eradication strategy, often used in the fight against HIV, can be foreseen in a different way, she added. “In people living with HIV and treated with antiretroviral therapy, we could use metformin to reactivate the reservoir cells responsible for viral replication upon treatment interruption, in combination with antibodies that are already used clinically and well tolerated. These antibodies can then detect the rare infected cells and eliminate them.” In the next phase of her research, Ancuta plans to launch a clinical trial to validate her in vitro research results, in collaboration with Finzi and their CRCHUM colleague Nicolas Chomont, and Jean-Pierre Routy of the McGill University Health Centre Research Institute. Before she can move forward with this strategy, she will test it in preclinical models. About this study “Metformin facilitates viral reservoir reactivation and their recognition by anti-HIV-1 envelope antibodies,” by Augustine Fert under the supervision of Petronela Ancuta et al., was published online in iScience on Aug. 8, 2024. The study received funding from the Canadian Institutes of Health Research, the Canadian Consortium for HIV Cure Research (CanCURE), the Canadian Foundation for AIDS Research (CANFAR), the International AIDS Society (IAS), the Fonds de recherche du Québec and the Fondation du CHUM. Also involved in the study were Dominique Gauchat, Philippe Ste-Onge and Gaël Dulude of the CRCHUM’s cytometry platform, and Olfa Debbeche and Laurent Knafo of the CRCHUM’s containment level 3 (CL3) platform, as well as Mario Legault of the Réseau VIH/SIDA-Maladies infectieuses. To read the original article click here.

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Tomato Concentrate Could Help Reduce Chronic Intestinal Inflammation Associated With HIV

AHA Publisher — Wed, 12 Jan 2022 08:00:28 +0000

University of California, Los Angeles (UCLA), Health Sciences via Newswise – New UCLA-led research in mice suggests that adding a certain type of tomato concentrate to the diet can reduce the intestinal inflammation that is associated with HIV. Left untreated, intestinal inflammation can accelerate arterial disease, which in turn can lead to heart attack and stroke. The findings provide clues to how the altered intestinal tract affects disease-causing inflammation in people with chronic HIV infection, suggesting that targeting the inflamed intestinal wall may be a novel way to prevent the systemic inflammation that persists even when antiviral therapy is effective in controlling a person’s HIV. The study is published in the peer-reviewed journal PLOS Pathogens. “Inflammation is an important process that protects the body from invading infections and toxins,” said Dr. Theodoros Kelesidis, the paper’s senior author and an associate professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA. “But in individuals who are successfully treated for HIV to the point that their viral load is no longer detectable, the continuing low-grade inflammation in the cells of the intestine contributes to an increased risk of heart attack or stroke.” People with HIV have been found to have a condition called “leaky gut,” in which products in the gut bacteria, such as lipopolysaccharides, move to other parts of the body through the bloodstream. Those products promote systemic inflammation and can accelerate coronary disease, Kelesidis said. The researchers worked with mice that had been infected with HIV and whose immune systems had been altered to mimic those of humans. The mice were fed a diet containing the tomato concentrate Tg6F, while the rest were fed a normal diet for mice — low in fat, cholesterol and calories. Tg6F comes from a specific type of genetically modified tomato; it contains anti-inflammatory and antioxidant peptides called apoA-I mimetic peptides, which imitate the main protein in HDL, the so-called “good cholesterol.” The researchers examined proteins called cytokines and chemokines that are known to predict intestinal and blood inflammation, which can augur adverse outcomes for people with chronic HIV infection. They found that mice that were given Tg6F had lower levels of pro-inflammatory cytokines and chemokines in their gut and blood than the mice that received the standard diet. In addition, they discovered that Tg6F prevented an increase in levels of a protein called ADAM17, which orchestrates inflammatory responses in people with chronic HIV infection. The investigators confirmed the anti-inflammatory effects of apoA-I mimetics in gut biopsies from people with HIV. “Targeting the inflamed intestine with the peptide that mimics the main protein in HDL may be a way of preventing systemic inflammation in people with chronic HIV,” Kelesidis said. “Giving oral apoA-I mimetics together with oral antivirals may be an attractive novel therapy to treat inflammation and prevent disease and death in HIV.” The authors note in the paper that mice cannot fully recreate all aspects of humans’ HIV infection. Also, the gut biopsies used to test the effects of apoA-I mimetics do not fully reflect how inflammation works within a living human body. To read the original article click here.

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An Antidiabetic Helps the Immune System Recognize Reservoirs of HIV

Tomato Concentrate Could Help Reduce Chronic Intestinal Inflammation Associated With HIV