Researchers at Brigham Young University and Johns Hopkins School of Medicine have confirmed a third type of human cell "reservoir" that harbors HIV in its infectious state, eluding treatments designed to kill the virus.

Follicular dendritic cells (FDCs), located in lymphoid tissues throughout the body, trap the virus on their surface. Because the trapped virus doesn't exhibit behavior that is looked for by medications targeting HIV — replicating, mutating, etc. — it escapes the treatment's killing attention, according to Greg Burton, BYU professor of chemistry and biochemistry.

The research, funded by the National Institutes of Health and the American Foundation for AIDS Research, will appear in Journal of Virology in June.

The discovery helps explain why treatments initially thought to be curative weren't, Burton said.

"In the mid-'90s, we had the wonderful advent of very potent anti-HIV drugs, and when people were treated with these, the virus amount in the body went to below detectable levels," he said, leading some researchers to call them a "cure."

When treatment stopped, viral counts rebounded to pretreatment levels in a couple of weeks. Study of viral DNA showed it was not, as suspected, a drug-resistance problem. Rather, it appeared that there were reservoirs where the virus remained in an infectious state, unharmed by treatment.

FDCs join two previously identified reservoirs: macrophages and latently infected CD4+ T cells.

FDCs store material needed to maintain the immune system's antibodies, releasing proteins to trigger production of specific antibodies if their numbers are low.

Burton says an FDC looks like a little octopus, with fragile long arms that grab the surrounding tissue, making it very hard to break into. The researchers figured out how to sample the virus in the reservoir and learned that it not only was stored in an infectious state, but also provided a point-in-time picture of the virus in various mutations.

The various forms of the virus they found on the surface of the cells indicates that the virus doesn't mutate in the FDC, but rather it acquires new samples over the course of time.

The human samples were provided by HIV-infected subjects at Johns Hopkins. Once the researchers figured out how to "break in" and get the stored material, BYU biologist Keith Crandall built a family tree to establish a time frame for the different viral versions.

Next, BYU graduate Trever Burgon, now seeking his doctorate at Stanford School of Medicine, sequenced individual HIV genomes from the FDCs to compare with samples taken from elsewhere in the body.

The FDC, believed to be the largest of the reservoirs, also has beneficial functions. If you get a tetanus shot, for instance, that shot clears out in about 72 hours. But the body's immune system remembers it for up to 10 years, and the researchers believe it does so by trapping and keeping samples of the antigenic material, which it releases a little bit at a time, introducing another round for antibody production. HIV takes advantage of the mechanism, staying active for a very long time while avoiding treatment that would kill it and continuing to come in contact with and infecting other cells.

Burton believes that while it can store the virus in infectious form to reignite infection under certain conditions, it can also provide scientists the information they will need to specifically target the virus that's stored on the FDC.

"If we could go in and perhaps flush it from the surface of the cell, we might decrease dramatically the amount of virus that could perpetuate infection," Burton said.

Because the FDC participates in other processes, the researchers believe the ramifications could stretch to conditions such as allergy and autoimmune disease. That, however, is fodder for future research.

The BYU and Johns Hopkins researchers are seeking an NIH grant to see if they can devise ways to attack the viral reservoir on the FDCs.


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