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AIDS virus: The movie

When AIDS first surfaced more than 25 years ago, researchers quickly realized that its cause, HIV, was spread by the bodily fluids of an infected person during intimate, often sexual, contact.

These fluids, rich in both naked virus and cells that were infected with virus, must trigger a chain reaction of infection. HIV reproduces inside (and then kills) a type of immune cell called the T cell. Unless each infected cell passes virus to several new cells, the infection will die out instead of advancing to the immune-destroying AIDS.

The movement of HIV, however, carries a curious kicker: Although naked viral particles can infect immune cells, virus-infected cells are thousands of times better at infecting immune cells.

The monochrome synapse junction has wavy borders and is about 600 nanometers in length
An electron microscope shows viral buds accumulating at a synapse between two immune cells. These buds allow HIV to move from the infected donor cell to the healthy target. (nm = nanometer; 1 billion nm = 1 meter).
All images courtesy Benjamin Chen, Mt. Sinai School of Medicine.

Caught in the act

Interestingly, a related pathogen called human T-lymphotrophic virus 1 is even less able to spread in its naked state. HTLV-1 causes leukemia and auto-immune disease, and about six years ago, scientists began to suspect that it could jump between cells that are in direct contact.

The researchers dubbed this cell-to-cell contact a "virological synapse." ("Synapse" originally referred to tiny gaps that enable signals to pass between nerve cells; a viral synapse, in contrast, transfers virus, not nerve signals.)

Now, Benjamin Chen, an assistant professor of infectious disease at Mt. Sinai School of Medicine in New York City, has used a high-tech video microscope to watch HIV passing across virological synapses in human T cells in a lab dish.

High speed video shows HIV moving across a "virological synapse" between two immune cells. The opening photo is a still of two T (immune) cells; outline shows a contact forming between them. The fluorescent viral protein then enters the contact, and the viral material enters the target cells. The outlines of the recipient (target) cell are not visible. Elapsed time is shown in minutes:seconds.

As the videotape rolls, we see viral particles -- lit up courtesy of fluorescent labels -- gather near the donor cell's surface, as buds form on the source side of a synapse. After a healthy immune cell moves into position, a batch of virus jumps across the synapse, transferring the infection.

The video shows the momentouns process of HIV infection as shot by Chen's collaborators at the Center for Biophotonics at the University of California at Davis.

And leave the driving to us

Studying the videos, Chen triggered a radar gun and clocked the virus at 0.2 to 0.8 microns per second. That sounds sluggish, but a virus is only 0.1 micron long, so they are moving up to eight lengths per second.

Do the math for a six-foot person, and that equates to an ultra-sprint: 33 miles an hour.

Viruses are foot-free parasites, so they do what comes naturally: commandeer a free ride from the motor proteins that normally transport freight inside cells, says Chen. "This is occurring with a very active involvement of cell machinery."

In some experiments, the virus was entering the healthy cell less than an hour after first contact between the cells.

In videos and electron micrographs, Chen and his colleagues saw the virus enter the recipient cell through the process of endocytosis. To envision this process, imagine pushing a walnut into a balloon until the balloon material somehow engulfs the nut and detaches from the outer wall. Or recall the bubble-inside-a-bubble formation you sometimes get with soap bubbles.

The target cells look like eyes with red scleras and bright green pupils, which are the synapses
A 3-dimensional view of an HIV-infected immune cell forming "synapses" with three target cells. HIV (shown by green fluorescent tags) has moved across the gap to infect the nearby cells.

In the immune cell, endocytosis forms a container called a vesicle that contains AIDS virus. Yet although endocytosis is a fundamental process of cell biology, Chen says, "most current models for HIV think about viral entry from the cell surface, rather than from an internal compartment within the cell."

Still, he adds, virologists are starting to suspect that most viruses enter cells through endocytosis.

The study “is a significant advance in understanding how HIV propagates from one cell to the next cell,” according to Vincent Piguet, who studies the movement of HIV in the department of dermatology at University Hospitals and Medical School of Geneva (Switzerland). “What is new here is the fact that the authors could follow with live microscopy the movements of HIV from one T cell to the next T cell across the virological synapse. Their study has implications for the prevention of HIV spread and potential new treatments that would target the virological synapse that forms between an infected T cell and an uninfected T cell.”

The payoff

HIV’s easy movement among T cells could explain the continuing failure of HIV vaccines, which have tried to teach the immune system to attack naked HIV. Tactics that combat a virus outside a cell may fail against a virus inside a cell, so it could be equally important to prevent cell-to-cell transmission. "If we can develop therapies or vaccines that target both modes of infection, we might have better success" at stopping the AIDS epidemic, Chen says.

- David J. Tenenbaum

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• Quantitative 3D-video Microscopy of HIV Transfer Across T-Cell Virological Synapses, Wolfgang Hübner et al, Science, Mar. 27, 2009.

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