Attacking HIV – new strategy to defeat HIV – Brief Article
How can a virus that hides in the very cells meant to ward off viral attacks be defeated? One promising strategy aims to destroy HIV within our own immune cells.
In the first six months of 1997, deaths from AIDS in the United States dropped more than 40 percent below the toll for the same period in 1996. AIDS is becoming a manageable chronic condition for some people. But the drugs used to treat it are expensive, costing up to $12,000 a year, and they do not cure the disease, Nor do they work for everyone. “It’s pretty clear at this point that drug therapy is not uniformly successful,” says Wayne Marasco, an infectious-disease specialist at the Dana-Farber Cancer Institute in Boston. Also, he says, even short drag holidays allow the virus to rebound, so people need lifelong therapy.
The AIDS virus is particularly insidious because it hides in the one place where antibodies cannot attack it: in the body’s immune cells themselves. But Marasco may have found a way to destroy HIV in its lair. He has designed antibodies that attack HIV inside T cells and has already succeeded in making some T cells immune to HIV. These internal antibodies, or intrabodies, as he calls them, may in the not-too-distant future lead to a unique form of gene therapy for HIV infection: regular infusion of genetically engineered HIV-resistant T cells into patients.
Marasco’s intrabodies home in on one particular HIV gene. This gene encodes a protein called Tat, which has several functions. First, once HIV has invaded a cell, the Tat protein recruits the host cell’s enzymes to jump-start the duplication of yet more viral RNA. Infected cells also disgorge Tat. If uninfected cells take it up, they become more vulnerable to infection by the virus. Tat also appears to increase T cells’ susceptibility, to suicide. Thus Tat not only helps HIV gain a foothold within immune cells, it also slowly weakens them.
Marasco created his intrabodies in a series of steps. First he injected Tat into mice and harvested the B cells that produced antibodies against the Tat protein. Then he fused those B cells with tumor cells to ensure a steady supply of antibodies for Tat. Next he took the gene that codes for the antibody’s binding site–the region on the antibody that recognizes and latches onto Tat–and inserted it into a harmless retrovirus, which delivered it to T cells taken from both HIV-infected and uninfected people. “The retrovirus is like a taxicab that drops a passenger off,” explains Marasco. “It drops the genetic information off by causing it to permanently integrate into the chromosome of the T cell.”
The T cells could now produce their own anti-Tat intrabody. Marasco found that uninfected T cells engineered to possess the intrabody were protected from attack by HIV. In infected cells, the levels of a key structural protein of HIV dropped dramatically, evidence that HIV replication was hindered. The intrabody apparently works by binding to Tat, jamming a site on its surface and preventing it from entering T cell nuclei, where viral replication occurs. The intrabody also feeds Tat into proteasomes, the cellular waste-disposal units.
Can Marasco’s altered T cells help people fend off the virus? He hopes to begin finding out this fall, when the first stage of his gene therapy trial starts. First he’ll remove white blood cells from ten AIDS patients whose drug therapy is no longer working. Then he’ll isolate their T cells and add the intrabody to some. Those T cells–plus others without the intrabody–will be injected back into the patients’ blood and their fates tracked. “We hope to show that the cells that express the anti-Tat gene have a longer survival in the patients than the cells that don’t,” explains Marasco. If that can be proved, he will take the study further.
Ideally, says Marasco, every few months patients would be Wen a dose of their own T cells that had been engineered to carry the intrabody. “Alternatively,” he says, “you could introduce the intrabody gene into stem cells”–precursors to T cells that divide indefinitely–“which when given back to the patients have the ability not only to self-replicate but to give rise to progeny that would carry that gene. We want the T cells to be a dead end for HIV.”
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