One of HIV's most insidious properties is its ability to influence virtually every part of the human immune system. Antibody-producing B cells, for example, begin to malfunction early after people become infected with HIV, for reasons that have been poorly understood. In a study released today, however, researchers identify specific alterations that occur in B cells when HIV levels are high - changes that disappear when patients are treated with antiretroviral drugs. The study, which appears in the current Proceedings of the National Academy of Sciences Early Edition online, is the first to define a unique subset of B cells in people infected with HIV.
Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) and a principal author of the paper, is all too familiar with HIV's effects on his patients' immune systems. "Their B cells produce excessive amounts of nonessential antibodies, fail to respond properly to normal physiologic signals, and are at increased risk of becoming cancerous," he explains. "Because their B cells do not work properly, people with HIV are left with fewer means to fight off the opportunistic infections that we see in full-blown AIDS."
B cells produce antibodies, proteins that specifically recognize and attach to foreign molecules, or antigens, such as those found on the surface of an invading virus or bacterium. Once they've hitched themselves to an antigen, antibodies either directly block the microbe from spreading or act as chemical beacons, signaling other immune system components to eliminate the captured organism.
To learn how HIV affects B cells, researchers from Dr. Fauci's laboratory studied the immune systems of people who were infected with the virus. Susan Moir, Ph.D., Angela Malaspina, Ph.D., and colleagues looked at B cells both before and after patients were treated with antiretroviral therapy. The researchers found consistent changes in B cells that occurred when HIV levels in the blood were high.
"At high virus levels, people had a large number of totally dysfunctional B cells," says Dr. Moir. "When we treated the patients to reduce their virus levels, the B cells reverted to their typical ways." When the researchers analyzed the B cells in detail, they found a specific change that might help explain the cells' loss of function: decreased amounts of a protein called CD21.
CD21 is a molecule on the surface of B cells that attaches to an immune system protein called complement. Dr. Moir and colleagues studied the cells with low amounts of CD21 and found these cells were unable to respond to many different B-cell stimuli in test tubes, yet spontaneously produced large quantities of irrelevant antibodies. Both of these properties are seen in the B cells of people with HIV. The researchers had previously shown HIV can hitch a ride on B cells by attaching to CD21, providing further support for the protein's possible role in HIV-induced B-cell malfunction (see news release at http://www.niaid.nih.gov/newsroom/hivbcell.htm).
"When we studied the cells further, they looked something like plasma cells that couldn't quite make up their minds," says Dr. Moir. Plasma cells are B cells that, upon recognizing an antigen, rapidly divide and pump out thousands of antibody molecules to attack a microbial invader. As B cells become plasma cells they change shape, lose their CD21 and stop responding to many B cell stimuli. "The B cells in patients with high virus levels look like plasma cells under the microscope, have very little CD21, and don't divide in response to chemical signals," Dr. Moir continues, "but in other respects they retain features of their parent B cells."
The researchers believe HIV causes changes to occur in B cells that either partially transition them to plasma cells or stimulate them to undergo changes along a completely different biochemical pathway. By identifying a specific change that links HIV levels with B-cell malfunction, Drs. Moir, Malaspina and colleagues have a key tool to further investigate how the virus is causing B cells to go awry.
"We know it happens, we know what drives it, and we know what the consequences are," says Dr. Moir. "This is the very first step in learning how we might be able to prevent it and improve the care of people infected with HIV."
The study was funded by NIAID and the National Cancer Institute (NCI). Researchers from NCI and the George Washington University also assisted in the study.
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov/.