Dean A. Haycock
Special To BioWorld Today
It's comic book code for expressing the rapid fire of a machine gun. It also contains an unintended clue about the way the AIDS virus manages to cut down T cells in the body's immune system.
The clue lies in the letter "tat." First, it is necessary to recall the AIDS virus, HIV-1, attacks activated T cells.
"Immune cells under normal conditions are quiescent, waiting to be called to duty by antigen presenting cells. Normally a small number become committed to fight a given invader. When the job is done, they 'commit suicide,'" or undergo apoptosis, explained Chiang Li, a research associate at the Dana-Farber Cancer Center and Harvard University School of Medicine in Boston.
Resting T cells, however, are no use to the AIDS virus. Only activated T cells are suitable for HIV-1 replication. Because the virus kills T cells during the process of replication, it needs to replenish the pool of activated, and therefore virus-susceptible, immune system cells. The virus' continued survival depenends on its ability to recruit more activated T cells from the large population of resting T cells.
That is where Tat comes in. Isolated in the early 1980's, Tat derives its name from "transactivator," a description of the protein's role as a transcription factor.
Li, Arthur Pardee, professor of biological chemistry and molecular biology, and their co-workers at the Dana-Farber Cancer Institute and the Harvard Medical School, have found that HIV-infected T cells secrete a Tat protein that signals quiescent T cells to become activated.
"This activation is like a 'wake-up' signal for the 'sleeping' immune cells," Li said.
Li is the first author of a paper entitled "Tat protein induces self-perpetuating permissivity for productive HIV-1 infection." The report appears in today's issue of the Proceedings of the National Academy of Sciences (PNAS).
By activating T cells, the Tat protein makes them susceptible to invasion by HIV-1 and contributes to the progression of the disease. Eventually, the AIDS virus can decrease the number of immune cells to levels so low the body is unable to fight off infections from microbes that are normally easily kept in check by the immune system.
Last year in an article in Nature Medicine, Gideon Goldstein, president of Thymon, in Short Hills, N.J., reviewed the relationship of Tat and HIV. He discussed the evidence that HIV-infected cells secrete Tat proteins, that T cells have a powerful uptake mechanism for the protein and that interdiction of this process could inhibit infection.
"This piece of work (by Li et al.) is a very excellent and precise analysis of the mechanisms by which Tat does it, and the effects on the particular enzymes and markers associated with the activation," Goldstein said.
The report is particularly interesting to Goldstein because he has postulated a vaccine to interdict the extracellular passage of Tat and the PNAS paper is further evidence of the mechanism by which such a vaccine would act.
"In terms of therapy, our whole approach is to look at host cells rather than at the virus itself. We are searching for therapeutic opportunity between the virus and immune cell interactions," Li said.
Li noted scientists now know a lot about the dynamics of the AIDS virus but very little about the dynamics of the T cell.
"Our model provides at least three steps for intervention. You can find compounds to block activity of Tat protein per se. Because Tat interacts with integrin receptors on T cells, you can also target that. We also have evidence for the intracellular signal transduction, so you also might look for a compound that might block infection at that stage," Li said.
Next Step Involves Targeting T Cell Activation
A top priority of the Boston researchers now is to identify compounds or to develop antibodies to block the activation of immune cells. Meanwhile, they are trying to learn more about the pathways that underlie this mechanism of activation. According to the results published in the PNAS paper, they have already established that activation of T cells by the Tat protein involves integrin receptors.
Furthermore, the work identifies important enzymes involved in the processes that carry the message from the receptor to the interior of the cells. These signal transduction components are identified as mitogen-activated protein kinases including ERK1 and JRK kinases.
All of these pieces of the virus's Tat activation scheme are potential targets for therapeutic intervention. The integrin receptor, however, offers a particularly enticing target since it already has been established in the literature that different integrins can be blocked.
"As a class of molecules, integrins are perceived to be excellent targets for intervention. Different integrins are involved in clotting, angiogenesis, allergy and asthma. All sorts of companies are trying to block the function of those integrins. So they are good targets. The functions of the integrins that interact with Tat proteins would potentially be an interesting target as well," said Martin Hemler, professor of pathology at the Dana-Farber Cancer Institute.
Hemler added that integrin blockers are now advancing in clinical trials and have even reached the market in the case of platelet integrins. Also, the receptor is the kind for which companies can design small molecule drugs. "That is why it is potentially a good target," Hemler said.
In the mean time, Li and his co-workers are trying to move their work from the cell culture level to the whole animal level of testing, Li told BioWorld Today.
The authors note in the discussion of their paper that preliminary in vivo experiments support the in vitro work. *