How HIV Enters an Immune Cell
HIV destroys the Immune system by targeting key cells called helper T cells. In the 1990s scientists learned that HIV gains entry to these cells by latching onto a protein on the cell's surface called CCR5 (top panel). A few people are able to withstand infection with HIV, however, because they lack a functional gene that codes for CCR5. Researchers hope that disabling the CCR5 gene (bottom panel) in HIV+ individuals might allow them to better control and perhaps even clear the infection.
Since the earliest years of the epidemic, a cure has been the elusive "holy grail" of HIV/AIDS research. Several false starts and failed attempts gave rise to pessimism, and as efforts focused on improving antiretroviral therapy (ART) and managing its complications, the idea of HIV eradication faded into the background.
In recent years, anti-viral drugs have reached the limit of their effectiveness. The cost of providing universal access has become unsustainable, and accumulating evidence underscores the detrimental effects of persistent HIV infection even while plasma viral load is low and CD4 cells count high.
Researchers are exploring many approaches for eradicating HIV, or achieving a functional cure, most of which can be categorized into several broad areas.
Many approaches have been initiated by scientists in an attempt to find a strategy to turbocharge the immune system against HIV. The first step is to find a way to keep HIV from being able to enter its favorite host cells, CD4+, also known as helper T cells. This particular T cell serves as the quarterback of the immune response by coordinating the interaction among many different types of immune cells.
When HIV first infects a helper T cell, the virus does not cause any real harm. Then later on, when the immune cells are activated to fight an ongoing infection, it instead dispenses more HIV copies. Even more unfortunate, HIV eventually kills these coordinating cells as well, depleting the immune system's ability to fight many other infections. In this way, HIV selectively eliminates the immune system's best-trained defensive players, and as they decline, so too does the body's ability to fight infections. AIDS, the end stage marked by deadly infections, then sets in.
At Baylor College of Medicine In Texas a group of scientists led by Michael Brenner began to experiment in improving methods for growing T cells outside the body. Using blood samples from HIV+ volunteers, they mixed these samples with small, tiny magnetic beads that acted as artificial dendritic cells. Dendritic cells normally instruct T cells to mature and multiply dramatically. By replenishing these magnetic beads every two weeks a colony of active T cells can be induced to multiply for more than two months having significant ability to deflect HIV advances.
At the same time, several laboratories reported the discovery of a protein known as CCR5 which sits on the surface of helper T cells and certain other cells, and acts like a doorway allowing HIV to gain entry. Furthermore, the scientists showed that individuals that naturally lacked the protein did not become infected. The discovery of CCR5's role in HIV infection helped to explain why the artificially grown T cells proved resistant. Somehow, the activation of the T cells by the beads caused the cells to shut down their production of CCR5 proteins. Without an access doorway, HIV was unable to enter the cells, and blocking the CCR5 receptor is the basis for an entirely new class of anti-HIV medication.
This discovery led to a cure strategy that received the most widespread attention, namely, gene therapy to protect susceptible cells from HIV infection. The method involves disabling the gene responsible for expression of the CCR5 receptor in human cells.
A San Francisco biotechnology company will be taking preliminary steps in conducting human clinical trials using T cells that have been genetically modified to seek out and attack HIV infected cells. These are same type of T cells that had been expanded in number using the magnetic bead technique.
A number of clinical trials have begun using infusions with CCR5 T cells modified into HIV+ volunteers. The study shows that the treatment is protecting the T cells, and moreover, the newly altered T cells will be tested for the ability to fight off HIV particles that are already present in the body.
Only a few years ago the idea of developing safe, effective and less expensive therapies that offer long term, drug free control of HIV was a vision that few even dared to dream of. The CCR5 re-engineered T cells are the most promising therapeutic innovation in thirty years.
In summary, research to date on HIV eradication, and the more likely achievable goal of a functional cure, has spotlighted several promising conceptual proofs. But before a cure is established, state of the art antiretroviral therapy is the best way to prepare and take advantage of combating HIV. Beginning treatment early, staying on treatment and keeping the HIV virus undetectable and under control, will make the patient most likely to be successful with a future cure strategy.
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