Trojan Horse-like mechanism may hold key to new HIV knowledgeMay. 7, 2003, 4:16 PM
In the battle against AIDS, the virus that causes it has proved a stealthy foe. The ability of HIV to evade the body’s defenses and lurk in unknown recesses has long baffled scientists and stymied their efforts to develop effective drugs and vaccines.
New findings from collaborating researchers at Vanderbilt University Medical Center, the University of Illinois, Chicago, and the National Cancer Institute provide evidence of a Trojan Horse-like mechanism whereby HIV infiltrates the immune system undetected and then exploits the system to promote its own survival.
The study, published online yesterday in Science, describes how the transmission of HIV is facilitated through a critical "infectious synapse," created by concentrating virus, receptor and co-receptor at the tight junction that forms between two specialized immune cells.
"I see this synapse as the center of the world for the immune response," says Dr. Derya Unutmaz, assistant professor of Microbiology and Immunology. "That’s where all the decisions are made…whether you will have a useful immune response, a harmful immune response, or a useless immune response."
With HIV, the response falls somewhere between useful and useless. The immune system does mount an initially strong response, Unutmaz says, but something happens that causes the defense to fall short of the goal of total extinction.
It’s all about subterfuge, really. To gain a foothold in the body, HIV enters the system through specialized immune cells called dendritic cells, which serve as scouts in the defense system, scanning mucosal tissues and mopping up any encountered bacteria and viruses.
Normally, once a virus is engulfed, enzymes within the dendritic cell chop it up and use the pieces to alert other soldier immune cells — the T cells — that an invader has been captured. In the case of HIV, dendritic cells capture it just as they would any other virus, but HIV remains somehow invisible to enzymatic destruction. Scientists have learned that the virus can hide there, unharmed, for days before the dendritic cell links up with a T cell.
What happens next is the subject of the current study. Using remarkable time-lapse microscopy, the researchers found that the "cloaked" virus particles rapidly stream toward the surface of the dendritic cell at the point of interaction with a T cell. At that same point of contact, the T cell concentrates HIV entry receptors, including CD4, CCR5, and CXCR4, which allow the virus to slip undetected across the junction, into the T cell.
Passing from the dendritic cell to the T cell is not sufficient for the virus to launch a productive infection, however. The T cell must be activated, which means that molecular signals passing between the two cells across this "infectious synapse" must trigger the T cell to begin the process of dividing and proliferating into an army of clones, which would be the normal response to battle an invading pathogen.
Once HIV moves inside the T cell, however, the cell doesn’t have time to begin its proliferation. The virus takes over the cellular machinery, turning it into a factory for its own reproduction. Eventually, the T cell is killed, releasing viral progeny and furthering HIV infection.
"So in a way what we have is a two-punch model," says Unutmaz, "where the virus exploits both its capture and presentation to a T cell, and at the same time utilizes dendritic cells to activate the T cell, making a perfect environment for its own benefit."
Unutmaz and his collaborators believe their model opens up a number of possibilities in the way of drug or vaccine design, from preventing capture of the virus to interfering with the ability of the virus to become "cloaked" to preventing transport across the cell junction.
"If we come to understand these mechanisms precisely, and how the virus utilizes these mechanisms to exploit the immune system, we could come up with ways to plug the weak points and ways to potentiate the response against the virus," he says.
Understanding HIV infection also sheds light on normal immune function, adds Unutmaz. "I always say that HIV knows more about immunology than I do," he laughs. "Understanding how it utilizes these mechanisms, we learn more about how dendritic cells talk to T cells. And that, of course, has a wider range of implications in designing vaccines against a variety of pathogens, not just HIV."
Recent studies have implicated the same dendritic cell receptor that captures HIV in Ebola virus, hepatitis C, and cytomegalovirus, among others.
Vanderbilt research assistant Stacy M. Bohks participated in the experimental work and co-authored the publication. The study was supported by grants from the National Institutes of Health.
Media contact: Mary Beth Gardiner, 615-322-4747 firstname.lastname@example.org