Even when coated with antibodies, HIV trapped by specialized lymph node cells remains infectious, according to researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID). Ensnared viruses may ambush critical immune cells that migrate through the lymph node, a scenario that provides a possible explanation for the large quantities of HIV and HIV-infected cells found in the lymph nodes of people with HIV disease, many of whom have abundant anti-HIV antibodies.
As reported in the Oct. 26, 1995 Nature, Gregory F. Burton, Ph.D., and colleagues at Virginia Commonwealth University in Richmond found that HIV, when attached to the external surface of lymph node cells called follicular dendritic cells, infected CD4+ T cells even in the presence of a vast excess of neutralizing antibodies. In the absence of follicular dendritic cells, similar quantities of neutralizing antibodies blocked the infectivity of the virus.
Although the precise mechanisms remain unclear, Dr. Burton and his colleagues observed the ability of follicular dendritic cells to facilitate HIV infection in the presence of neutralizing antibodies in a laboratory model based on human cells, and in mice.
These important findings build on previous data that demonstrate that the lymphoid organs are central to the pathogenesis of HIV disease," says Anthony S. Fauci, M.D., NIAID director.
A commentary on the paper by the Virginia Commonwealth group, written by Dr. Fauci and Lewis K. Schrager, M.D., of NIAID's Division of AIDS, appears in the same issue of Nature.
Follicular dendritic cells have thread-like tentacles and are found in lymph nodes and related organs such as the tonsils and spleen, within hot spots of immune activity called germinal centers. These cells act as flypaper, trapping invading pathogens (including HIV) and holding them in the germinal centers until B cells come along and initiate an immune response. Close on the heels of B cells are CD4+ T cells, which rush into the germinal centers to help the B cells fight the invaders.
CD4+ T cells are the primary targets of HIV," explains Dr. Fauci. "These cells may become infected as they enter the germinal center and encounter HIV trapped on follicular dendritic cells." Once infected, CD4+ T cells may leave the germinal center and infect many other CD4+ T cells that congregate in the region of the lymph node surrounding the germinal center.
Paradoxically, the networks of follicular dendritic cells in the germinal centers, by doing their normal job of trapping pathogens and initiating an immune response, may be an important reason why HIV is so effective at destroying the immune system," says Dr. Schrager. "By trapping HIV, the follicular dendritic cells expose a steady stream of CD4+ T cells to the virus, which, as Dr. Burton's work tells us, appears to be infectious even in the presence of neutralizing antibodies."
In previous studies, NIAID scientists have studied the lymph nodes of HIV-infected individuals and found large amounts of HIV in germinal centers in the early stages of disease, both in infected cells and as "free" virus bound to follicular dendritic cells. Over time, large quantities of HIV accumulate in the lymph nodes, ultimately overwhelming the germinal centers, leading to the destruction of the follicular dendritic cells and their trapping function, as well as the rest of the lymph node. This may preclude a successful immune response against other pathogens as well as HIV.
"Taken together, recent studies of the interactions between HIV and follicular dendritic cells in lymph node germinal centers may have important therapeutic implications," says Dr. Schrager. "It may be possible, for instance, to prevent the virus from becoming trapped in the first place or to remove the entangled virus from the follicular dendritic cells. These and other related questions need to be explored further in animal models."
Dr. Burton's co-authors, all from Virginia Commonwealth University, include Sonya L. Heath, M.S., J. Grant Tew, B.S., John G. Tew, Ph.D., and Andras K. Szakal, Ph.D.
NIAID, a component of the National Institutes of Health, supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad. NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.