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Monkey T-Cells Don't Express Co-receptor

Sooty mangabey monkeys with SIV do not experience disease progression because their CD4 T-cells express little of the CCR5 co-receptor the virus requires to enter cells.

Some species of non-human primates, including sooty mangabeys, can become infected with SIV (a simian virus closely related to HIV) but never experience disease progression including CD4 cell loss and collapsing immune function.

Researchers have studied such monkeys since the early years of the epidemic, hoping to uncover clues that might be used to help people fight HIV. Now, as reported in the June 26, 2011, issue of Nature Medicine, researchers have discovered that CD4 T-cells of infected mangabeys do not up-regulate expression of CCR5 co-receptors on their surface, thus blocking viral entry.

Below is an edited excerpt from a press release issued by Emory University describing the research and its findings.

SIV-Resistant Monkeys Close the Gates to Viral Infection

Sooty mangabeys, a type of African monkey, have intrigued scientists for years because they can survive infection by SIV, a relative of HIV, and not succumb to AIDS.

Researchers have identified a way some of sooty mangabeys' immune cells resist infection: they close the gates that SIV and HIV use to get into the cell. The findings may lead to strategies to help HIV-infected individuals cope better with infection.

The results are published online in the journal Nature Medicine.

"We have shown sooty mangabeys can prevent SIV from infecting a very important part of the immune system," says first author Mirko Paiardini, PhD, senior research scientist at Yerkes National Primate Research Center, Emory University. "This protection from infection comes from reducing the levels on the cell surface of a molecule that SIV uses to enter the cell."

Co-first author is postdoctoral fellow Barbara Cervasi. The senior author is Guido Silvestri, MD, chief of microbiology and immunology at Yerkes National Primate Research Center, Emory University. Collaborators included investigators from NIH, University of Pennsylvania, University of Pittsburgh and University Hospital Ulm.

To infect a cell, HIV and SIV need to find two molecules on the cell's surface. Scientists call these molecules co-receptors, and they can be thought of as gates. One of the co-receptors is CD4, which appears on immune cells called T cells. The other is called CCR5. Stimulating a T cell usually increases the level of CCR5, facilitating infection.

Paiardini, Cervasi and their colleagues found that in sooty mangabeys, a type of T cell called a central memory T cell doesn't turn on CCR5. This means that even when a sooty mangabey is infected with SIV, some T cells can mostly avoid being killed by the virus.

Memory T cells help the immune system respond to an infection faster and stronger the second time around. Central memory T cells are long-lived and found in lymph nodes, in contrast to effector memory T cells, which have shorter life spans and are found mostly in tissues, such as the intestines, Paiardini says.

"Not all T cells are created equal," he says. "Some appear to be more important than others for keeping the immune system up and running. This is why having central memory T cells resistant to infection is so valuable. By protecting central memory T cells, sooty mangabeys avoid the loss of T cells and the chronic immune activation that are the hallmarks of AIDS in humans."

Scientists have identified several differences in the pattern of infection between sooty mangabeys and both humans and rhesus macaques, a monkey that is susceptible to SIV infection.

"For several years, we and others thought lack of chronic immune activation was the main factor protecting sooty mangabeys from AIDS," Paiardini says. "This study changes this working model and proposes that lack of immune activation in sooty mangabey is secondary, deriving from their ability to protect and maintain their central memory T cells."

Paiardini continues, "We would have not been able to perform such complex comparative studies without the presence of the large colony of sooty mangabeys at the Yerkes National Primate Research Center."

Investigator affiliations: Yerkes National Primate Research Center, Emory Vaccine Center and Department of Pathology, Emory University, Atlanta, GA; Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA; University of Urbino, Urbino, Italy; Laboratory of Molecular Microbiology, US National Institutes of Health, Bethesda, MD: Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia; Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA; Institute of Molecular Virology, University Hospital Ulm, Ulm, Germany.

7/5/11

Reference
M Paiardini, B Cervasi, E Reyes-Aviles, et al. Low levels of SIV infection in sooty mangabey central memory CD4(+) T cells are associated with limited CCR5 expression. Nature Medicine (abstract). June 26, 2011 (Epub ahead of print).

Other Source
Emory University. SIV-Resistant Monkeys Close the Gates to Viral Infection. Press release. June 26, 2011.