Researchers Show How HIV Enters Dendritic Cells and Spreads to CD4 T-Cells

A receptor known as Siglec-1 on the surface of dendritic cells latches on to HIV's outer membrane and enables the virus to enter these cells, which carry it to lymphoid organs where it can infect neighboring CD4 T-cells, according to research published in the December 18, 2012, edition of PLoS Biology.

CD4 cells are the primary target of HIV, but dendritic cells play a key role in capturing the virus as it enters the body and transporting it to lymph nodes and other locations, where it comes into contact with many vulnerable CD4 cells.

Nuria Izquierdo-Useros from AIDS Research Institute IrsiCaixa in Barcelona and colleagues determined more precisely how this occurs, which could inform future treatment strategies. "We suggest that this natural pathway through mature dendritic cells, which would normally lead to antigen processing and presentation, has been subverted by HIV-1 for its own storage and transmission," the researchers wrote.

Below is an edited excerpt from a press release issued by IrsiCaixa describing the research and its findings in more detail (translated from Catalan).

Researchers Discover How the AIDS Virus Enters Key Immune Cells

• Scientists from the AIDS Research Institute IrsiCaixa have identified how HIV enters the cells of the immune system responsible for the dispersion of the virus inside the body.
• The new work identifies the molecule located on these cells that is responsible for HIV capture. It allows the internalization of the virus within these cells, called dendritic cells, which act as a "Trojan horse" to disperse the virus inside the body.
• The discovery opens the doors to a new family of drugs that could block these molecules. These new drugs would complement current treatments, which do not act on this mechanism of dispersion of the virus.

Barcelona -- December 13, 2012 -- One of the reasons why we still do not have a cure for HIV infection yet is that the virus infects cells of the immune system that activate the response that should stop infection. In concrete terms, the main HIV targets are white blood cells named CD4 T lymphocytes, so called because they have the protein CD4 on their membrane. While we have more than 20 different HIV drugs available today, all of them act blocking the cycle that HIV follows to infect those CD4 T lymphocytes, but they do not manage to eliminate all virus from the body. The available treatments do not fully act on another kind of immune cell, called dendritic cells, which HIV also penetrates, remaining almost fully infectious. Dendritic cells are responsible for activating the immune response, but when they do so the HIV they carry can also infect CD4 T lymphocytes. Therefore, dendritic cells harboring the virus promote the spread of infection within the body.

Now, scientists from the AIDS Research Institute IrsiCaixa, funded by "la Caixa" Foundation and the Health Department of the Government Generalitat de Catalunya (autonomous Catalan government), have identified the door that HIV uses to enter dendritic cells, an enigma the scientific community had been trying to solve for years. The work will be published in the December 18 edition of the international journal PLoS Biology. The research was also supported by the HIVACAT Program for the research and development of a vaccine against AIDS.

These results are the latest milestone in a research program led by the IrsiCaixa researchers Javier Martínez-Picado and Nuria Izquierdo-Useros, in collaboration with research groups from Heidelberg University in Germany (coordinated by Hans-Georg Kräusslich) and the University of Lausanne in Switzerland (led by Amalio Telenti). This team published another paper in PLoS Biology this past April, in which they identified molecules called gangliosides,located on the surface of HIV, that are responsible for viral entry into dendritic cells. The new results identify the molecule on the surface of dendritic cells that captures HIV, allowing the virus to spread throughout the body and come in contact with T lymphocytes. "We had the key and now we have found the lock," said Martínez-Picado. "The enigma is solved. Now we are already working on the development of a drug that could block this process to improve on the efficacy of existing treatments against AIDS."

"We have observed that the protein that acts as a lock for the entrance of HIV could also facilitate the entrance of other viruses, and therefore our results could also lead to the development of treatments for other infections that exploit this mechanism," added Izquierdo-Useros.

In order to identify the precise molecule on the membrane of dendritic cells capable of capturing HIV, the researchers studied a family of proteins present on the surface of those cells, called Siglecs. It is known that these proteins bind to gangliosideson HIV. In a laboratory study, scientists mixed virus with dendritic cells that displayed different quantities of Siglec-1. They concluded that when the amount of Siglec-1 on the surface of dendritic cells increased, these cells captured more viruses, which in turn allowed for enhanced spread of virus to target CD4 T lymphocytes.

The researchers also performed another experiment in which they inhibited the Siglec-1 protein, either coupling it with antibodies or blocking the expression of the corresponding gene. They found that the dendritic cells lost their capacity to capture HIV and, more importantly, also lost their ability to transfer HIV to CD4 T lymphocytes. With all these data, the scientists concluded that Siglec-1 is the molecule responsible for HIV entrance into dendritic cells, allowing for viral transmission to CD4 T lymphocytes, and could therefore become a new therapeutic target.

12/21/12

Reference

N Izquierdo-Useros, M Lorizate, MC puertas, et al. Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides. PLoS Biology10(12):e1001448. December 18, 2012

Other Source

AIDS Research Institute IrsiCaixa. Discovered How the AIDS Virus Enters Key Immune Cells. Press release. December 13, 2012.