Controlling A Killer, One Step At A time
Last week, we reviewed the lifecycle of the human immunodeficiency virus (HIV). Learning how the virus grows and develops has been crucial to developing medicines that control HIV infection. This knowledge has enabled drug discovery researchers to devise ways to interfere with the virus at critical points in its life, preventing it from infecting more of the patient’s white blood cells.
The resulting drugs—often referred to as highly active antiretroviral therapies (HAART)—manage AIDS well. Unfortunately, they don’t completely eliminate the virus that causes it. In other words, they’re not a cure. In addition, HIV’s high rate of mutation means it rapidly evolves resistance to drugs that once kept symptoms at bay. For this reason, HAART typically combines different drugs which is the “cocktail” approach. This strategy takes advantage of the fact that viruses are unlikely to develop resistance to multiple drugs at once. Researchers continue to work on new drugs that can successfully fight infection when resistance emerges.
This WEEKLY looks at how some current HIV medications interrupt key stages of the viral lifecycle.
One Virus, Many Drugs
Existing HIV drugs work to prevent T-cell infection, viral replication, or the assembly and release of new viral particles. Examples of these strategies include:
- Preventing infection: HIV wipes out the immune system because it infects a critical type of white blood cell, helper T-cells. To gain entry to the T-cells, HIV binds a protein called CCR5 on the surface of those cells. Drugs that interfere with that interaction can prevent infection and are called CCR5 inhibitors. Currently, there is only one CCR5 inhibitor on the market—Maraviroc, a small molecule drug. CytoDyn (Vancouver, WA) has a monoclonal antibody inhibitor of CCR5 in Phase III clinical development. Another way to prevent infection is to block the HIV surface protein, GP120, from binding the CCR5 receptor. GlaxoSmithKline (London, UK) is conducting Phase III clinical testing of Fostemsavir, a small molecule which targets GP120, the portion of the viral surface protein that enables HIV to bind to and enter T-cells. Its developers believe that the bit of GP120 that Fostemsavir targets mutates slowly, perhaps reducing the chances that resistant strains of the virus will emerge. Peptide therapeutics also work on GP120. Roche’s Fuzeon interferes with the ability of a portion of GP120 to fuse with the T-cell membrane. (Article continues below)
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- Blocking viral replication: As described last week, two steps are critical for viral replication: conversion of the viral RNA genome into DNA by the viral enzyme reverse transcriptase (RT) and insertion of this DNA into the host cell genome by the viral enzyme integrase. The first antiviral drug approved by the FDA for the treatment of HIV in 1987, AZT, inhibited RT. Since then, many others have been approved, including Viread and Emtriva, both marketed by Gilead Sciences (Foster City, CA). Click here for a complete list of RT inhibitors. Integrase inhibitors include Isentress (Merck & Co.), Vitekta (Gilead Sciences), Tivicay (ViiV Healthcare), and Biktarvy (Gilead Sciences). All RT and integrase inhibitors are small molecule drugs.
- Disrupting viral assembly: After replication of its genome and production of new proteins, the final step of the HIV lifecycle is the assembly of new viruses. This process depends on a specific kind of viral protein called a protease. This enzyme processes newly-made viral proteins so that they can form new viral particles. Inhibiting the HIV protease enzyme means no new viral particles. Small molecule protease inhibitors on the market include Prezista (Janssen Therapeutics), Tipranavir (Boehringer Ingelheim), and Lexiva (GlaxoSmithKline).
The diagram below shows where in the HIV lifecycle each of these types of drugs act.
These drugs have profoundly improved the lives of people with AIDS around the world. However, the as-yet-undiscovered cure for AIDS may arise instead out of biotech. Check out these previous WEEKLY articles for an overview of gene therapy and genome editing approaches to tackling AIDS. Biotech never rests, and the quest for a cure pushes on.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.