They discover a molecular and cellular circuit capable of regulating reservoirs of latent AIDS viruses

The human immunodeficiency virus (HIV) is a pathogen that causes the progressive loss of CD4 lymphocytes (immune system cells involved in the response to infections) and, if not treated, leads to acquired immunodeficiency syndrome (AIDS). Although currently, treatment with antiretrovirals allows, in most cases, to keep virus replication at bay, stabilize the number of CD4 cells, prevent immunodeficiency and reduce mortality, until now it has not been possible to develop a therapy that makes it possible to completely eradicate the virus. Even in cases where treatment is successful and makes the viral load in the blood undetectable by standard tests, the virus persists in a latent state in a small group of cells and, in the event of interruption of therapy, can return. to replicate.

The development of therapies that allow achieving a sterilizing cure (the complete eradication of the viral load and of the body’s reservoirs) is one of the central objectives of those who investigate in the field of HIV. To achieve this goal, it is essential to better understand the dynamics of HIV reservoirs. In this sense, the experts are exploring both possible treatments consisting of attacking the cells in which the infection persists by reactivating the virus (which would make it possible to distinguish infected lymphocytes from non-infected ones), as well as others based on achieving a greater control and silencing of the viral reservoir.

In this sense, a recent study carried out by specialists from the National Council for Scientific and Technical Research (CONICET) in Argentina reveals the existence of a circuit that involves extracellular vesicles (nanometric-sized structures present in all body fluids, such as blood), cells of the immune system known as macrophages and galectin-1 (a protein that plays an important role in different pathologies), which reverses the latency of the virus and, in this way, modulates the activity and repopulation of the viral reservoir.

Many individuals living with HIV, even when receiving effective antiretroviral treatment, have a persistent activation of their immune system and a state of chronic inflammation. This situation is considered one of the keys that explain the persistence of the viral reservoir in people under treatment. Infected individuals, even though they may have a very long survival thanks to antiretroviral therapy, suffer from different health complications (cardiovascular, bone and metabolic) related to chronic inflammation. “In previous work we showed that, in HIV patients, extracellular vesicles stimulate macrophages to produce inflammation. In this investigation we saw that these extracellular vesicles also cause macrophages to express high levels of galectin-1 (Gal-1) and secrete it into the blood. But in addition, we detected that this galectin, by interacting with infected lymphocytes, reverses latency”, explains Matías Ostrowski, one of the study coordinators, as well as a CONICET researcher at the Institute for Biomedical Research on Retroviruses and AIDS (INBIRS). entity dependent on CONICET and the University of Buenos Aires (UBA).

Part of the research team. From left to right: Natalia Laufer, Omar Sued, Matías Ostrowski, Karina Mariño, Julia Rubione, Juan Stupirski, Gabriel Rabinovich and Alejandro Cagnoni. (Photo: Florencio Fiorini Foundation)

Although the reactivation of the viral reservoir induced by Gal-1 is not dangerous in terms of leading a person under treatment to immunodeficiency, it could be one of the impediments to the achievement of the sterilizing cure, that is, to the eradication of reservoirs of latent HIV. Achieving a sterilizing cure, on the other hand, could allow patients to stop treatment without the risk of the virus replicating again, as well as provide a solution to the pathogenesis linked to chronic inflammation.

“This leads to the question of whether blocking Gal-1 expression could help control reservoirs of latent HIV. On the contrary, another alternative would be to stimulate the expression of Gal-1 to ‘wake up’ the infected cells and attack them with other drugs”, explains CONICET researcher Gabriel Rabinovich, director of the Glycomedicine Laboratory of the Institute of Biology and Experimental Medicine. (IBYME) and also coordinator of the study.

What is interesting, in this sense, is that Rabinovich’s team at IBYME is working both on the development of an antibody that makes it possible to block Gal-1 (which could be used, for example, to treat certain tumors), as well as on the an agent that mimics or stimulates the production of this protein (which could serve to prevent autoimmune diseases).

This study arose as a collaboration between Ostrowski’s laboratory, a specialist in the role of extracellular vesicles in HIV-associated inflammation, and Gabriel Rabinovich’s team, which has been investigating the role of galectins for almost three decades ( especially Gal-1) in different physiological and pathological scenarios. The work is part of the doctoral thesis of the first author of the article, Julia Rubione, who between 2015 and 2020 was a CONICET doctoral fellow at INBIRS.

“The goal of this collaboration was to study whether Gal-1 had any role in HIV infection. Given that Gal-1 is an immunomodulator and has an anti-inflammatory function in many pathologies, we expected to find something on that side, but the results led us down a different path and we ended up discovering a role for Gal-1 that we had not known about until now”, comments Rabinovich, who is also a full professor of immunology at the Faculty of Exact and Natural Sciences of the University of Buenos Aires.

The tests carried out for this study included both the analysis of samples from different groups of patients with HIV, as well as the performance of in vitro experiments in cell cultures that involved tissues taken from individuals with HIV.

“The analysis of serum from different groups of patients allowed us to determine that there is a considerable increase in the normal levels of Gal-1 in circulation in the blood of individuals with HIV. In addition, we were able to associate the increase in Gal-1 levels with chronic inflammation in HIV patients, as well as with an increase in the transcriptional activity of the viral reservoir”, Rubione relates.

On the other hand, the comparison between the different groups of patients and the follow-up of infected individuals (before and after antiretroviral treatment) made it possible to rule out the existence of a correlation between the increase in Gal-1 and viral load, as well as with the CD4 lymphocyte count. No association was found between the increase in Gal-1 and the size of the reservoirs, although there was between the concentrations of the lectin and the transcriptional activity of the reservoirs.

“In a subsequent trial, in cell cultures, we studied the impact of extracellular vesicles on macrophages and found that vesicles from HIV patients induced the secretion of Gal-1 in much greater quantity than vesicles from healthy donors,” says Rubione. .

This experiment allowed the research team to confirm that the increase in Gal-1 in the blood of HIV patients is associated with the inflammatory phenomenon and the action of extracellular vesicles.

According to the researchers, the importance of the results obtained invites us to continue studying this new circuit, which could be key both to unravel the pathologies associated with chronic inflammation in patients with HIV and to design therapies that allow the modulation of viral reservoirs .

The study is titled “A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection. And it has been published in the academic journal mBio, of the American Society for Microbiology. (Source: Miguel Faigón / CONICET. CC BY 2.5 AR)