Protein mix-up tied to suppressed immune response early in HIV infection

February 22, 2002

CHAPEL HILL - New research that arose from a serendipitous laboratory observation could resolve a scientific mystery, the fact that some people become less able to fight HIV infection despite having a high number of "killer" immune cells circulating in the blood.

A report of the study currently appears in the Internet edition of the March 1 issue of the Journal of Immunology (see below for URL). The findings offer new complexity to HIV's impact on the immune system and, if confirmed, could also shape vaccine design for HIV prevention and treatment.

"One of the questions that we've not understood for a long time is why some people with HIV become immunocompromised before you would think they should; that is, while they still have significant numbers of CD4 and CD8 T cells," said senior study author Dr. Jeffrey A. Frelinger, Kenan Professor and chair of microbiology and immunology at the University of North Carolina at Chapel Hill School of Medicine.

CD4 Helper T-Cells are white blood cells that orchestrate the cellular immune response, providing help to other immune system cells. CD8 T cells are a type of cytotoxic T-lymphocyte (CTL) that kill cells in the body that have been infected by a foreign organism. These white cells recognize surface markers on other cells in the body that label those cells for destruction. In this way, CTLs help keep virus-infected cells in check.

But early in the disease process in some HIV-infected individuals, CD8 T cells apparently become unresponsive to HIV surface molecules, essentially not attacking them, well before any profound loss of CD4 Helper cells.

"It's like having many soldiers ready to fight for you, but the soldiers are so weak they cannot fight. They are not doing their work because something is stopping them," said Dr. Mohammed L. Garba, a postdoctoral researcher in Frelinger's laboratory and the study's principal author. That "something" Garba initially glimpsed while preparing an assay of human blood. He noticed that the CTLs of some people who were HIV-positive "made a really nice [immune] response" to vaccinia virus, the smallpox vaccine. In the same cell culture, when Garba introduced HIV protein molecules, the vaccinia-specific response was suppressed.

After further experimentation, Garba found that the CTLs of people who showed a suppressed vaccinia response do indeed make a response to HIV. "But instead of making molecules we know to be protective in viral infections -- molecules like interferon-gamma -- they make a molecule called TGF-beta, which is immunosuppressive," Frelinger said.

Moreover, the TGF-beta molecule is broadly suppressive. It can suppress not only HIV-specific immune responses but other responses as well, including influenza and other "opportunistic" infections that often are a threat to people with HIV.

The new study tested blood samples donated from 40 HIV patients at UNC and 20 samples from donors at low risk for HIV. All but one had been previously exposed to vaccinia due to small pox vaccination.

About 25 percent of HIV donors produced TGF-beta in response to stimulation with HIV proteins or peptides. This production of TGF-beta "was sufficient to significantly reduce the interferon-gamma response of CD8 cells to both HIV and vaccinia proteins," the report stated. However, introduction of antibodies to TGF-beta reversed the suppression.

According to the researchers, TGF-beta appears to be the dominant response among people whose immune cells produce both TGF-beta and interferon-gamma. Essentially, TGF-beta puts the brakes on an ongoing positive immune response to viral antigens, including HIV surface proteins.

"Certainly, the issue of TGF-beta in the immune response is important, particularly when designing immunotherapy for an individual," Frelinger said. "Our study has scientific value in terms of understanding HIV pathogenesis in that it provides an excellent explanation of how a positive immune response some people make is actively broadly immunosuppressive."

"The findings also provide a target for potential therapies that would interfere with this [TGF-beta] response, which would certainly be helpful for some individuals."
-end-
Along with Garba and Frelinger, UNC co-authors include Drs. Christopher D. Pilcher and Joseph Eron of the Department of Medicine and Dr. Andrea L. Bingham, School of Pharmacy.

For Internet access to the journal report, go to: http://www.jimmunol.org/content/vol168/issue5/index.shtml

Note: Additional Contact Frelinger at 919-966-2599, jfrelin@med.unc.edu

By LESLIE H. LANG
UNC School of Medicine

University of North Carolina Health Care

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