Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
|
|
The Wall Street Journal - 8 July 1996
Jerome Groopman
Imagine HIV as a villain that takes the immune system hostage. It does this by incorporating its own genetic blueprint into the nucleus of T-cells and macrophages (white cells that engulf microbes) and subverts them into producing new viruses instead of protecting against infection and cancer. Over time, the infected cells are killed by their captor. The host is unable to produce enough new cells to overcome the losses due to the virus.
During the past year the medical community was taken by surprise by the success of combining nucleosides like AZT and 3TC with the newly developed protease inhibitors -- enzymes that act like scissors to cut protein. Patients treated with these cocktails had decreases in virus production of ten- to one-hundred fold and striking increases in T-cell numbers. We learned from these clinical trials that when the virus is potently inhibited, the immune system has a remarkable capacity to regenerate. This knowledge makes the search for an AIDS cure into an engineering problem, a question of what further roadblocks need to be built to stop the virus in its tracks. Three new approaches will be considered most prominently in Vancouver.
One exploits the breakthrough in our understanding of how HIV attaches to the surface of T-cells and macrophages. Certain proteins that snake through the membrane of these cells, termed serpentine chemokine receptors, were recently discovered to act as docking sites for the virus in concert with a previously described surface protein called CD4. Blocking this first step in HIV's attack would limit the spread of the virus within the body and protect virgin cells from infection.
A second promising new approach focuses on a viral enzyme called integrase. This enzyme is essential for the insertion of the viral DNA blueprint into the nucleus of the T-cell and macrophage. Following the strategy that succeeded with the protease enzyme, the three dimensional structure of the integrase enzyme (a DNA-inserting enzyme) is being analyzed by high-performance computers. Chemical structures are being selected by computer modeling which fit into the clefts of the enzyme and block its function. Preventing the viral genes from integrating into the command center of the nucleus would restrain HIV from taking the cell hostage.
Yet another vulnerable part of the virus under consideration is the Rev protein. Rev acts as a guide transporting newly made viral genes from the cell nucleus into the cytoplasm where they are packaged into new viruses. Prototype Rev inhibitors have been created that put blinders on this guide. In laboratory experiments, they have successfully blocked exit of viral genes from the nucleus and shut off packaging of new viruses.
Not every promising target will be translated into an effective clinical therapy. And no one underestimates the virus's capacity to mutate to escape our treatments and to cause profound damage to a body's defenses. But the means exist to lock the virus firmly within the cell and to permit the immune system to function, free from assault. HIV, like a vicious killer, once unopposed and rampant, may then be imprisoned. For life.
---
Dr. Groopman is professor of medicine at Harvard Medical School, chief of the hematology/oncology division at Deaconess Hospital and chief of experimental medicine at Beth Israel.
960708
WJ960705
Copyright © 1996 - The Wall Street Journal. Reproduction of this article (other than one copy for personal reference) must be cleared through the WSJ Permissions Desk.
AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Elton John AIDS Foundation UK, the National Library of Medicine, AIDS Walk of Orange County, and donations from users like you.
Always watch for outdated information. This article first appeared in 1996. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1980, 1996. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .