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University of Pittsburgh Schools of the Health Sciences

HIV Infection Requires An Accomplice: B Cells With Special Protein Direct HIV To T Cells, Research Finds

New pathway that may aid in treating, preventing HIV reported at AIDS 2006

TORONTO, August 12, 2006 — HIV infection of T cells requires activation of a molecule on the surface of B cells, a finding that reveals yet another pathway the virus uses in its insidious attack on the immune system, University of Pittsburgh researchers will report at the XVI International AIDS Conference (AIDS 2006).

“The research supports a new role for B cells in the development and spread of HIV between cells, with important implications for future studies and drug development efforts that focus on reservoirs of HIV in cells other than T cells,” said Charles R. Rinaldo, Jr., Ph.D., professor and chairman of the department of infectious diseases and microbiology at Pitt’s  Graduate School of Public Health (GSPH) and the study’s senior author.

Nearly all approved HIV drug regimens and most of those being tested in clinical trials focus on T cells of the immune system, where HIV replicates and thrives. HIV hijacks T cells by binding to a cell membrane molecule called CD4 and to either or both of two other receptors, from which the two strains of HIV, X4 and C5, take their names. Once anchored on the membrane, it’s able to slither inside and take command of the cell. But as the Pitt studies have found, there is an important first step in a new pathway involving B cells that express a protein called DC-SIGN. B cells are key players in an immune response.

While these cells themselves do not become infected, they play a pivotal role as an accomplice in HIV’s takeover of T cells.

According to the research to be reported by Giovanna Rappocciolo, Ph.D., research assistant professor of infectious diseases and microbiology at GSPH, laboratory studies provide evidence of DC-SIGN in subsets of B cells from both healthy subjects and HIV infected individuals and indicate DC-SIGN is both a point of entry for HIV and necessary for T cell infection.

B cells were isolated from blood samples obtained in 33 healthy subjects and 20 adult patients with HIV from the Multicenter AIDS Cohort Study (MACS). Researchers found about 8 percent of these cells expressed DC-SIGN.

In one set of studies involving cells from the healthy subjects, the team activated DC-SIGN using two molecules that T cells typically engage in their communication with B cells. Once activated, the DC-SIGN B cells were placed in a culture with T cells and a small amount of virus. Within 24 hours, HIV had begun invading the T cells, yet the B cells were spared. Although they did not become infected, B cells nonetheless harbored virus that was transmissible to T cells for up to two days. HIV had little effect on the T cells when B cells were not present in the culture. Pretreating the B cells with a molecule that blocks DC-SIGN before culturing them with both T cells and HIV was a deterrent against T cell infection as well, further proof that to invade T cells, HIV requires DC-SIGN to be expressed on B cells.

In addition to Drs. Rinaldo and Rappacciolo, other authors include Paulo Piazza, Ph.D., Craig L. Fuller, Ph.D., Todd A. Reinhart, D.Sc., Simon C. Watkins, Ph.D., David T. Rowe, Ph.D., Mariel Jais, Aki Hoji, B.S., and Phalguni Gupta, Ph.D.

The research was supported by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, both of the National Institutes of Health.

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