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Therapies In HIV Pipeline

Medicine has made gigantic strides in understanding and treating the human immunodeficiency virus (HIV) since its emergence in the early 1980s. Thanks to robust drug discovery efforts, today HIV is managed as a chronic disease instead of the death sentence of years past.

The secret to HIV’s infectious success lies in its high mutation rate. Developing drug resistance over time is the name of the game as viral proteins change just enough to escape detection, keeping researchers on their toes. In this issue, we’ll examine the drug industry’s persistence to stay ahead of HIV.

HIV Primer

HIV causes acquired immunodeficiency syndrome (AIDS) because it infects and disables T-cells, a critical type of white blood cell. This incredibly destructive power is carried out by just a handful of proteins and a lipid envelope encapsulating the RNA-based genetic material.

HIV Infection

HIV infiltrates T-cells in order to expand its grip on the immune system.

First introduced in the late 1980s, HIV drugs have been developed on scientists’ understanding of the viral life cycle. By deciphering key steps in viral infection and replication, researchers have been able to come up with drugs to stop the virus. Most HIV patients take a combination of drugs to control infection.

Targeting HIV

The mechanisms of action detailed above show the various ways approved drugs target HIV.

In Development

Bristol-Myers Squibb (New York, NY) has begun Phase III clinical testing of BMS-663068 which targets GP120, the portion of the viral surface protein that enables HIV to bind to and enter T-cells. A similar drug target—but only by proximity—is Roche’s (Basel, Switzerland) injectable Fuzeon, which targets the GP41 portion of the same viral surface protein. Even though both of the drugs are targeting nearby areas, the part of GP120 targeted by BMS-663068 mutates at a much lower rate than GP41, adding hope that resistant strains of the virus will be less likely to emerge.

All of the HIV drugs currently on the market are small molecule drugs, except for Fuzeon, which is a peptide, or a short chain of amino acids (the building blocks of proteins). Investigators at Rockefeller University (New York, NY) in collaboration with Celldex Therapeutics (Hampton, NJ) have initiated clinical trials of “broadly neutralizing” antibodies, or antibodies that recognize multiple strains of HIV, as both a therapeutic and a preventative measure.

The Vaccine Hope

The best way to prevent any infectious virus is through vaccination. Researchers have been trying to successfully develop an HIV vaccine for decades. Unfortunately, the same high mutation rate that empowers the virus to become resistant to drugs also enables it to evade immune responses potentially activated by vaccination.

Dr. Robert Gallo—a scientist who identified HIV as the cause of AIDS back in 1984—is pioneering a new approach to HIV vaccination at the University of Maryland’s Institute of Human Virology. Traditional vaccines work by injecting patients with an inactivated version of the virus, or with one protein from the viral surface, in hopes of training the immune system to produce antibodies to recognize and target the virus. When that target is constantly changing, training the immune system is somewhat of a moot point.

Instead of targeting the virus in its resting state, the University of Maryland vaccine targets the virus when it is in a transition state: the precise moment at which the virus binds to its CCR5 receptor on T-cells. During this transition, normally hidden parts of the GP120 protein are exposed. Because this part of the protein is critical for viral entry, it has a very low rate of mutation since most random mutations would make the virus less effective in cell entry.

Since this part of the GP120 protein is normally hidden, the immune system will not produce antibodies against it if the intact virus or GP120 protein is used as the vaccine. The trick is to stabilize the virus in the transitional state by linking the GP120 protein to a portion of the CD4 receptor. This forces the virus to take on the conformation in which the “hidden” parts are exposed, enabling the immune system to produce antibodies against this critical portion of the GP120 protein and prevent infection.

After years of testing in various animal models, University researchers—in collaboration with Profectus BioSciences (Baltimore, MD)—announced they were starting Phase I human clinical testing on the novel vaccine last October.

Making The Right Cut

The dance to stay ahead of HIV lingers on, but a new possibility might just stop the music. Sangamo Biosciences (Richmond, CA) is currently conducting Phase II clinical testing using genome editing to eradicate the virus from infected patients. The idea is simple: remove T-cells from infected patients and edit their genomes so that their T-cells no longer contain the CCR5 receptor. These edited T-cells are infused back into the patient’s body, where they reproduce and become the primary T-cell population. No CCR5 receptor, no HIV infection. No virus can survive outside of its host cell, so by making T-cells impossible to infect, the virus no longer has a host and will not survive. Genius!

Genome Editing HIV

Sangamo Therapeutics is using its genome-editing platform to disrupt the CCR5 gene on patients’ T-cells.

The leap from HIV being an unmanageable disease to a manageable one took a few decades. With the advent of new biotechnologies on the rise, it may be just a few more hops before we land on a true breakthrough against HIV.

 

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