2023-04-18 11:45:52
Human immunodeficiency virus (HIV) is a virus that attacks the body’s immune system. If left untreated, it can lead to acquired immunodeficiency syndrome (AIDS). As with other viruses, when a foreign substance enters our body, the immune system recognizes it as “non-self” and launches an immune response, in which various cells, tissues, and organs work together to identify, attack, and eliminate the foreign substance. foreign substance. In the case of the HIV virus, it first enters the body through dendritic cells, the immune cells that are in contact with the external environment, patrolling our bodies for pathogens and protecting us from infections.
Dendritic cells are those in charge of processing foreign proteins, molecules or particles and presenting them to the T cells of the immune system, acting as messengers and initiating the immune response.
A key element that helps dendritic cells recognize and bind to the virus is a group of membrane proteins responsible for distinguishing between self and non-self. One of those proteins, called Siglec-1, plays a key role in the early stages of HIV infection, specifically in the capture and transmission of the virus.
When HIV enters the body, the first thing it encounters are mucosal surfaces, where it binds to various molecules. Siglec-1-expressing dendritic cells can then capture and transmit the virus to other cells, initiating an immune response. But along this pathway, HIV particles can also use dendritic cells as vehicles to infect helper T cells, also known as CD4+ cells, further spreading the infection in a process known as transinfection. This means that although it can help start the immune response, it can also facilitate infection.
Although previous studies have previously identified Siglec-1 as the main receptor that binds to HIV particles on active dendritic cells, very little has been known about the precise mechanisms of how this occurs. Understanding the role of Siglec-1 in the immune response to HIV is critical to developing effective treatments and therapies for people living with HIV/AIDS.
A team of researchers has now succeeded in describing the mechanisms underlying the capture of HIV viruses in dendritic cells, and the role that Siglec-1 plays in the capture and trafficking of these viral particles. The study is the work of Enric Gutiérrez, Nicolás Mateos, Kyra Borgman and Fèlix Campelo, led by ICREA professor María García-Parajo, all from ICFO (Institute of Photonic Sciences) in the Barcelona town of Castelldefels, in collaboration with Susana Benet, from Germans Trias i Pujol Hospital and its Research Institute (IGTP), Carlo Manzo from the University of Vic (UVic) in Catalonia; Jon Nieto-Garai and Maier Lorizate from the University of the Basque Country (UPV/EHU), as well as Itziar Ekizia, Núria Izquierdo-Useros and Javier Martínez-Picado from IrsiCaixa, in Spain.
Using advanced techniques such as super-resolution microscopy and single particle scanning, the team studied the spatial organization of Siglec-1 in dendritic cell membranes and its role in the early stages of infection. Interestingly, they have seen that when dendritic cells are activated, Siglec-1 nanoclusters are formed, aggregates of these molecules, which are decisive for enhancing the capture of HIV-like particles. More importantly, virus binding via these Siglec-1 nanoclusters triggers a massive and global transformation of the dendritic cell actin cytoskeleton, leading to the formation of a single sac-shaped compartment. that accumulates viruses. It was previously known that these viral compartments are related to the spread and infection of T cells by the virus that leads to AIDS, but the mechanism that caused their formation was a mystery until now.
In addition, the researchers have discovered that the organization and mobility of these nanoclusters are regulated by actin polymerization, a key cellular process that plays an important role in various biological functions. They have also seen that both the formation of these nanoclusters and the confinement of the virus occur in specific regions of the cell membrane characterized by the activity of RhoA, a protein that also participates in actin polymerization.
Mature dendritic cell expressing Siglec-1 nanoclusters (green) on the cell surface a few minutes after the capture of HIV particles (red dots). Right: Massive transformation of cell morphology after 60 minutes of HIV uptake. (Image: ICFO. CC BY-NC)
The potential of super-resolution microscopy
Single-particle scanning and super-resolution microscopy techniques have allowed researchers to better understand the mechanisms that regulate the interaction between viruses and cells, especially the distribution and function of receptors. “Seeing is believing”, points out ICREA professor at ICFO María García-Parajo, “Most viruses are very small, with sizes around 100 nanometers, and therefore cannot be resolved using standard optical microscopy. Even The smaller the receptors they bind to on the cell membrane, thus the use of super-resolution microscopy and single-molecule imaging methods are crucial to directly visualize how viruses are taken up by cells, and allow researchers to follow their fate until the final infection of the immune cells.
As Javier Martínez-Picado, a researcher at IrsiCaixa, explains, “in 2012 IrsiCaixa discovered that Siglec-1 was a key protein that functions as an HIV binding receptor on the surface of certain immune cells, facilitating the spread of the virus in the body . However, how Siglec-1 captures the virus in these specific cells remains a mystery. The current results help us to draw a more accurate picture of HIV uptake by these cells and to develop new tools to block this mechanism.”
Although the exact role of Siglec-1 in the context of HIV-1 infection remains an area of active investigation, and further studies are required to fully assess the complex interactions and its potential as a therapeutic target, these findings offer valuable insights into the complex interactions between the virus and the immune system.
The study is titled “Actin-regulated Siglec-1 nanoclustering influences HIV-1 capture and virus-containing compartment formation in dendritic cells”. And it has been published in the academic journal eLife. (Source: ICFO)
#Discoveries #early #stages #AIDS #virus #infection #human #body