Noting that Vpr mimics the actions of a class of steroidal drugs called glucocorticoids, the researchers hypothesized that Vpr might act through the same molecular pathway -- binding to the same receptors -- as those drugs. Glucocorticoids are used as chemotherapeutic agents against some cancers and autoimmune disorders, but are also known to inhibit cytokine production and to induce cell death in lymphocytes, the category of immune cells to which macrophages and T cells are belong.
To test this possibility, the researchers conducted experiments with the antisteroidal compound RU-486, perhaps better known for its use in Europe as an abortion-inducing agent, to see if that drug could counter the effects of Vpr. They added Vpr to populations of cultured lymphocytes in the laboratory, documented its impact, and then added RU-486 to see if the results were altered in any way.
"When we added RU-486 to our cell cultures, it markedly reversed many of the effects of Vpr," says Velpandi Ayyavoo, PhD, lead author on the study and a research associate in Weiner's laboratory. "These results suggest that antisteroids such as RU-486 should be considered for development as potential HIV therapies."
The cytokines suppressed by Vpr include tumor necrosis factor (TNF) alpha and the interleukins IL-2, IL-4, IL-10, and IL-12. Because glucocorticoids are known to suppress nuclear factor kappa-B, a gene transcription factor that regulates cytokine production, the scientists examined the effects of Vpr on nuclear factor kappa-B. They found that Vpr activated another factor called inhibitor of kappa-B to neutralize nuclear factor kappa-B, largely shutting down production of the cytokines.
In addition to Weiner and Ayyavoo, coauthors based at Penn include S.
Mahalingam, PhD; Sagar Kudchodkar, PhD; and William V. Williams, MD. The
remaining coauthors are Artin Mahboubi, MS, and Douglas R. Green, PhD, at the La
Jolla
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Contact: Franklin Hoke or Karen Kreeger
media@mail.med.upenn.edu
215-662-2560
University of Pennsylvania School of Medicine
1-Oct-1997