Saturday, November 26, 2022

Advances against HIV: Argentine scientists discover a mechanism that controls latent virus in patients


Julia Rubion was examining protein levels in samples from people with the HIV virus. They expected to find notable differences between people based on the stage of infection and whether or not they were on treatment. But the hypothesis wasn’t valid: There was an increase in protein levels beyond the differences between the people studied.

We had to go out and find a reason, and the answer lay in the discovery of a regulatory circuit that keeps the HIV virus secreted in reservoirs within the human body, one of the main barriers to eliminating infection.

“It was a circular investigation with surprising results coming and going,” Rubion told InfoBay to refer to the process by which a regulatory circuit was described that promotes reversal of virus latency in infected cells. gives. The work was published in mBio, the specialized journal of the American Society for Microbiology.

This was a study that was part of Rubion’s doctoral thesis as a Concise fellow and in which researchers from Argentina, Chile and Australia participated. It provides an important discovery for the great pending challenge facing humanity today: the eradication of HIV.

Since 1996, people living with HIV have benefited from the development and access to antiretroviral therapy, which has led to a drastic reduction in morbidity and mortality. However, antiretroviral treatment does not eliminate the virus from the body.

The virus can persist in the white blood cells of the immune system, which are CD4 T cells as the main viral reservoir. Laboratories in various countries are now exploring ways to develop interventions against these viral reservoirs.

Rubion’s work, with the coordination of Matias Ostrovsky from the Institute of Biomedical and Retrovirus Research (INBIRS), from the Faculty of Medicine of the University of Buenos Aires and Coniset, and Gabriel Rabinovich from the Institute of Biology and Experimental Medicine of Conisette and UBA’s Faculty of Exact and Natural Sciences, has also contributed to the viral Contributed new knowledge to better understand the persistence and dynamics of the reservoir.

And it opened up the possibility of moving forward to the evaluation of drugs targeting the protein, called galectin 1, which Rubian and his colleagues found at increased levels in both people with access to treatment and those without medication.

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The first step the research team took was to evaluate blood samples from 51 people living with HIV and another 13 who did not have it. They found that people with the virus had “significantly higher” amounts of the galectin 1 protein. They classified the group of people living with HIV into 4 subgroups: those who had just been diagnosed, those who had chronic infections and those without treatment, those who were in treatment, and elite controllers, who were able to control the infection after therapy. succeeded in ,

They found that protein levels were high in all subgroups and did not change over time regardless of an individual’s viral load and treatment status. Through various analyses, they found that high concentrations of the protein are associated with inflammation and transcriptional activity of virus reservoirs in people.

But what kept the protein high? The next step was to unravel that secret. From previous research, they knew that small structures secreted by cells, known as extracellular vesicles, can increase inflammation when they encounter macrophages, a type of white blood cell in the immune system. .

“By analyzing and comparing blood samples from people with HIV and those without the virus, it was possible to determine that there is a regulation circuit of the viral reservoir. In people with HIV, extracellular vesicles induce an increase in galectin production after encountering macrophages. In turn, the activity of this protein can cause the virus to reproduce in latency”, Rubion said.

There are other mechanisms that have been described by other researchers to understand the regulation of the viral reservoir. Last May, a team from the Université Libre de Bruxelles in Belgium posted in the journal eBioMedicine that the UHRF1 protein is also involved in keeping HIV inactive.

Two potential pharmacological strategies have also been proposed on what can be done with the viral reservoir in the future. One of them suggests that future treatments should kill cells reactivated by HIV and prevent other cells from becoming infected. Another option would be to put the virus into a deeply dormant state so that it does not reactivate. “Preclinical studies are needed to find out whether it is appropriate to increase or block the galectin 1 protein to modify the circuit and eliminate the secreted reservoir,” explained Dr. Rabinovich.

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Consulted by Infobae, researcher Marcelo Loso, director of the immunocompromised service responsible for the field of emerging diseases at the Ramos Mejia Hospital in Buenos Aires, Argentina, commented on the research he did not participate in: “At work, scientists are working on the activation of transcription factors. Hypothesize the role of the protein galectin 1 as a promoter and eventual reversal of the latency state of HIV. This is interesting, but will require more studies to confirm.” The expert said: “Right now, there are dozens of well-established hypotheses about HIV reservoirs. Eliminating the viral reservoir has been proposed as a key to the eradication of HIV, but there is much debate about whether to evaluate those reservoirs. What is the best way to do .

Conisette and UBA scientists, Paula Perez, Alejandro Zernicier, Gabriel Duet, Federico Pehuen Pereira Gerber, Jimena Salido, Martina Fabiano, Yanina Ghiglione, Gabriela Turk, Natalia Laufer, Alejandro Cagnoni, Juan Perez also participated in the work published in MBO. Joaquin Merlo, Carla Pascual, Karina Marino and Juan Stupirsky. Omar Sood collaborated with the HUSPEED Foundation (now part of the Pan American Health Organization) as scientific director. Also part of the team were Manuel Varas-Godoy from Universidad San Sebastián in Chile and Sharon Levin from Monash University in Australia.

The published research was carried out with public and private financial support. Funding was provided by: the National Agency for the Promotion of Research, Technological Development and Innovation, the National Institutes of Health and the Johns Hopkins University of the United States, Bunge & Bourne, Sales, the Williams & Barron Foundation, and the Ferrioli and Ostri from Argentina.

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