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New Generation of HIV Drugs
 The new generation of HIV drugs, called entry inhibitors, come in three varieties. The fusion inhibitors, which are farthest along in development, prevent melding of the viral envelope to the cell membrane. The other two classes of entry inhibitors are the attachment inhibitors and co-receptor inhibitors.
T-20 leads this growing pack of fusion inhibitor drug candidates. Even though in vitro tests show that HIV can resist T-20, too, combining the new drug with others, in powerful new cocktails, should buy years of time for many people, because of the complementary activity of drugs using different mechanisms. T-20 may even become part of cocktails that include drugs further down the pipeline. At least one other type of entry inhibitor shows impressive synergy when administered with T-20 in vitro—that is, the combination is even more effective than either new drug alone.
And so a much-needed new arsenal against AIDS is waiting in the wings. Thirty percent of patients abandon existing drug cocktails because of side effects, complex treatment regimens, or interactions with other drugs. In contrast, T-20’s side effects are primarily at the injection site and no drug interactions have been identified. “Simply adding drugs to the antiretroviral cocktail does not help people with resistant HIV, and there is potential for serious drug toxicity with so many medications. Several therapies being tested show promise, including ... the fusion inhibitors T-20 and T-1249,” says Julio Montaner, a professor of medicine at the University of British Columbia and co-director of the Canadian HIV Trials Network in Vancouver.
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Introducing Fusion Inhibitors
The road to T-20 began in 1989, when Tom Matthews, an associate professor and member of Bolognesi’s research group at the AIDS Center at Duke University, was looking for molecules on the HIV envelope that might serve as a vaccine. Such molecules attract the attention of the immune system because of the way that they fold. HIV contacts a vulnerable cell’s CD4 receptors with molecules of glycoprotein 120 (gp120) that jut from the viral envelope like lollipops. (A glycoprotein consists of a sugar bound to a protein.) Another glycoprotein, gp41, anchors the gp120 molecules in the envelope.
Matthews was seeking a molecule common to many strains of the virus, so that a vaccine would work against a broad range of viral variants. And he came upon a part of gp41 that looked a little like a stretch of amino acids (a peptide) that flu virus uses to infect cells. So Matthews synthesized that part of gp41, but instead of auditioning it for a role as a vaccine, he decided to put it on T cells growing in culture to see what would happen. “Tom decided to see if it had any antiviral activity. And lo and behold, it did! Not only was it active, it was very active. He came racing upstairs saying, ‘I think we have something very worthwhile here!’” recalls Bolognesi.
It is natural for a scientist to doubt a spectacular result, so Matthews repeated the experiments over and over—and found repeatedly that the peptide indeed blocked infection. “In the early 1990s we published a series of papers, and others became interested. Now we know this to be at the heart of the mechanism that the virus uses to enter cells,” says Bolognesi. By 1993, preliminary studies in animals showed that enough of T-20 could be given to lower viral load (the number of viruses in the bloodstream, the primary measure of infection status).
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