Tissue in monkeys infected with a close relative of HIV can ramp up production of a type of T cell that actually weakens the body's attack against the invading virus. The discovery, in lymph nodes draining the intestinal tract, could help explain how the HIV virus evades the body's immune defenses.
If the same pattern is found in people infected with HIV, the finding could lead to a treatment strategy that slows the production of this restraining type of T cell. This would let the immune soldiers go after the virus more aggressively.
The scientists don't know if the simian virus is directly causing the build-up of the inhibitory T cells, called regulatory T cells, but in any case, reducing regulatory T-cell production could boost the body's resistance to the evasive virus.
The research was a collaboration among scientists at the Cincinnati Children's Hospital, UC Davis School of Medicine, and the California National Primate Center.
Regulatory T cells, or Tregs, normally tamp down immune-system attacks, presumably to prevent an over-active assault that can cause harmful inflammation or auto-immune disease. The scientists suspect that the high number of Treg cells in the infected primates might prevent their immune systems from mounting a full-on attack against the virus.
The researchers focused on immune cells called dendritic cells that interact with Tregs in preparation for their policing duty. This occurs in lymph nodes throughout the body's lymphatic system -- the part of the circulatory system that also drains many organs of fluids, fatty acids and other substances.
The study found that mature dendritic cells were particularly active in promoting Treg production, and that these promoters were in high concentration in nodes draining the intestine, or mucosa. The intestinal mucosa is the site of early infection and aggressive transmission for both the primate virus and HIV, making it the first line of defense against the invasion.
"The intestinal mucosa contains highly activated 'helper' T-cells that are prime targets for the HIV virus, so it is important to understand how the body fights HIV in this under-studied tissue," said Barbara Shacklett, associate professor of medical microbiology and immunology.
Shacklett is a co-author of a paper on the research, entitled "Myeloid dendritic cells isolated from tissues of SIV-infected Rhesus macaques promote the induction of regulatory T cells," published in the journal AIDS. An editorial in the same issue of AIDS highlights the new research and related studies that are clarifying the interaction between the simian version of HIV and the Treg cells that can control attacks against them.
The studies were led by the research lab of Claire Chougnet in Cincinnati, which has studied regulatory T-cells for many years and is focusing on their role in such diverse situations as HIV infection and human aging. Pietro Presicce, postdoctoral fellow in Chougnet's laboratory at the Cincinnati Children's Hospital Research Foundation, performed the studies along with Julia Shaw, a graduate student in Shacklett's laboratory at UC Davis. Christopher Miller of the California National Primate Research Center, a noted researcher on animal models for HIV infection, also collaborated on the study.
The authors stressed that Tregs usually increase when the immune system is at risk of over-reacting. Their high numbers lead to a reduced immune attack, although the mechanism is not well understood. But in persistent infections -- when a strong immune response is called for -- Tregs should decrease in number, taking a "hands-off" approach and freeing the immune army to advance. HIV may sabotage this control by prompting increased Treg production as if the body need not rally its defenses against the virus.
The research was supported in part by the California National Primate Research Center's Pilot Project award funded by BaseGrant NCRR-RR-000169 and the National Institutes of Health grants AI8227, AI068524 and AI057020.