The human immunodeficiency virus (HIV) devastates the body's ability to fight off infection by destroying a key class of T cells essential for maintaining a vigorous immune response. Now, scientists from the National Institute of Allergy and Infectious Diseases (NIAID) report for the first time that B cells-the antibody-producing cells of the immune system-help ferry HIV throughout the blood and can likely deliver the virus to nearby T cells. This discovery, reported in the September 4 issue of the Journal of Experimental Medicine, helps explain several phenomena associated with HIV infection and paves the way for new approaches to eliminating the virus from the blood.
"This study enhances our understanding of how HIV persists in the body and might partly explain the abnormalities seen in B-cell function in people with HIV infection," says Anthony S. Fauci, M.D., NIAID director and chief of the laboratory where the research took place. "Identifying this pool of HIV-carrying cells also opens new avenues for treating the infection."
The research, conducted by Susan Moir, Ph.D., Angela Malaspina, Ph.D., and colleagues from NIAID's Laboratory of Immunoregulation, follows reports from several laboratories that HIV can infect B cells in the test tube and that low levels of HIV genetic material can exist in B cells of HIV-infected individuals. None of these reports, however, have identified viable HIV associated with the B cells of infected individuals.
To address this concern, the researchers isolated B cells from the blood of people with chronic HIV infection. When they examined these cells for the presence of HIV, they found significant levels of the virus attached to the surface of the cells. The scientists then used test-tube experiments to show the virus could infect T cells under laboratory conditions.
Because of the close interaction between B and T cells in the immune system, this discovery casts new light on how HIV can interact with T cells. The two cell types constantly form temporary attachments with each other to exchange information and coordinate the immune response. This gives the B cells ample opportunity to pass HIV to previously uninfected T cells. Dr. Moir explains that B cells are not a hidden reservoir of HIV, however, because they do not house internalized, replicating virus, and the amount of B-cell-bound virus decreases as HIV levels decline in the blood. "HIV does not appear to reproduce inside B cells, but rather hitches a ride on the cell surface so it is free to jump to nearby T cells." The studies also might explain why B-cell-mediated immunity in individuals with chronic HIV infections can go awry.
"People with high levels of HIV in the blood often have malfunctions in their B cell responses, such as uncontrolled activation of antibody production," explains Dr. Moir. "In the past, scientists have thought this was caused largely by indirect effects of HIV infection, but now we have evidence that some B cell abnormalities might be due to direct viral interference."
Dr. Moir and co-workers looked at the B cells carefully to determine how the virus attached to the cells. They identified the docking point for HIV, a molecule called CD21. This protein appears on the surface of B cells and normally binds complement, a molecule that tags invading microbes and targets them for destruction. The researchers discovered that HIV, when attached to complement, could use CD21 as a binding site on the B cell. Because complement normally "tickles" CD21, thereby signaling B cells to produce antibodies, the scientists believe the uncontrolled production of multiple antibodies in people with HIV might be caused by the repeated stimulation of the B cell as the virus binds CD21.
Now that the researchers have shown how B cells might play a role in HIV infection, they are testing to see if the HIV in infected T cells is genetically related to that on the B cells. They are also pursuing more studies on how HIV might directly cause deficiencies in B-cell function. "Scientists haven't looked at B cells much during HIV infection," says Dr. Moir, "This research opens a new opportunity for better understanding the complex nature of the disease."
Scientists from the National Cancer Institute and Advanced BioScience Laboratories, Inc., Kensington, Maryland, also participated in this study.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
S Moir, et al. B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med 192(5):637-45 (2000). This article is available online at http://www.jem.org/cgi/content/full/192/5/637.
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