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By Tim Stoddard

	Paul Skolnik Photo by Fred Sway

When HIV ravages the immune system, even the most benign microbes are potentially deadly. Patients with full-blown AIDS are at high risk of developing opportunistic infections, most commonly in the lungs, but also in the mouth, the eyes, and the brain. Lung infections are a hallmark of AIDS, but they are surprisingly understudied, because until recently most researchers believed they understood how HIV disarms the immune system and sets the stage for infection. But if Paul Skolnik’s hunch is correct, that long-held paradigm is about to change.

Skolnik, a MED professor of medicine and the founding director of BUMC’s Center for HIV/AIDS Care and Research, is leading an innovative research effort to better understand how HIV disables the lung’s defenses. Researchers have long known that HIV attacks T-helper cells, which play a central role in the immune response by marshaling other cells to attack foreign invaders. It was assumed that in the absence of T-helper cells, the lungs were left undefended, allowing common bacteria and viruses and fungi to run riot. But Skolnik believes HIV is demobilizing the lung’s defenses in another way altogether.

For the past 20 years, HIV research has focused primarily on how the virus affects the so-called adaptive arm of the immune system, which is composed of antibodies and white blood cells that cruise the bloodstream identifying and killing infected cells. But very little is known about how HIV compromises the more primitive innate defenses of the immune system, which include a slew of simpler responses to infection. One of these is phagocytosis, where cells called monocytes rush into a site of infection and engulf foreign invaders. Skolnik’s team is now blazing a new path in HIV research by exploring how HIV affects alveolar macrophages, monocytes that reside in the lungs, and prevents them from protecting the lungs.
Skolnik’s hypothesis is that HIV corrupts certain pattern recognition proteins on the surface of the lung’s monocytes that recognize pathogens. Without these surface receptors, the monocytes don’t get the message that there’s an infection. It sounds simple enough, but in the realm of HIV research, the proposal has been a radical leap forward. It was daring -- and sound -- enough to have received one of 21 Innovation Grants for AIDS Research from the National Institute of Allergy and Infectious Disease, a branch of the National Institutes of Health. The two-year, $300,000 grants support novel, high-risk research that promises to advance AIDS research. Many of the projects don’t pan out, Skolnik says, “but when they do, they have the potential to change the paradigm of HIV immunology.”
With Marlynne Quigg-Nicol, a MED research associate in the department of medicine’s section of infectious diseases, Skolnik and his colleagues are looking closely at what HIV does to the surface topography of the lung’s monocytes. For the past 10 years, scientists have known that the various cells in the body are covered with proteins called Toll-like receptors. (The receptors were discovered and named by a German biologist; “toll” is German slang for “cool.”) When monocytes bump into a foreign body, their Toll-like receptors “feel” its surface. If the pattern touches a certain combination of Toll-like receptors, the monocyte springs into action, preventing further damage.

Skolnik’s team already has preliminary evidence that HIV infection tweaks two kinds of Toll-like receptors on the lung’s monocytes. But with the Innovation Grant, team members are now collecting lung samples from HIV-positive and HIV-negative subjects to determine how HIV tampers with these receptors. It’s not clear, for instance, whether HIV simply sticks to the outside of the Toll-like receptors and gums them up, or if the virus actually invades the macrophages and coerces them to make faulty receptors.
As they probe these questions, they will also explore ways of making it easier for other researchers to continue this work in the future. Collecting lung samples is tedious and expensive, so Skolnik’s group is looking at whether researchers can study Toll-like receptors in generic cells that have been specially grown for laboratory use. These cell lines, called U1 and U937, are shipped to researchers around the world. Skolnik’s team will compare the Toll-like receptors in the patient-derived lung samples with those from the U937 and U1 cells to see if the cell lines are accurate models for the changes that happen to macrophages during HIV infection.
The ultimate goal of the research is to understand how HIV prevents alveolar macrophages from doing their job. With that information in hand, researchers may be able to develop innovative therapies to keep the Toll-like receptors functioning. “If we can understand why these alterations are taking place,” Skolnik says, “maybe one day we’ll be able to devise strategies to block those changes from happening and to reverse them.”

17 October 2003
Boston University
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