Possible new HIV therapies, and the potential for a cure

Antiretroviral medications have been at the forefront of HIV treatment for years. Used in multi-drug combinations, they’ve been effective in controlling HIV infections by acting synergistically to lower the number of circulating HIV particles — to undetectable levels in many patients.

These drugs have prolonged the lives of many of those with all over the world, but they don’t cure HIV. They don’t cure HIV because some HIV infects specific cells in the immune system, and can then remain dormant there. Over time, this HIV from some of the infected cells can become active again, replicate and be released into the bloodstream. This cycle can keep repeating such that the virus will always eventually reappear. The antiretrovirals suppress the virus, but if the drugs are stopped, the virus returns to the blood. The antiretrovirals and the patient’s immune system hold the virus in check, but neither side wins.

Researchers have been working for years to try to end this stalemate. Recently a few new techniques have been developed that may help with the problem. None of these techniques represent a cure in and of themselves. But, perhaps, if used in conjunction with each other and the antiretrovirals, they may be able to produce a cure in the future.

Broadly Neutralizing Antibodies (BNAs)

HIV is a shapeshifter virus. It mutates often. Some of these mutations affect the surface of the protein outer coat of the virus. At times, when that happens, the antibodies that the patient has made to destroy the HIV will no longer work. These antibodies have specific structures that mate with reciprocal structures on the virus. When that reciprocal structure changes, the antibody fails to attach to the HIV particle. When that happens, the HIV isn’t cleared by the body and the virus can then remain in the blood infecting other cells. It can continue to infect at least until the immune system retaliates by shapeshifting on its own to produce new, effective antibodies.

Scientists have discovered that there are some antibodies against HIV that aren’t limited to a single, small site. That is, these antibodies don’t focus on just a small part of the HIV coat. They look at larger pieces of this shell. These antibodies can still work even when mutations cause small changes in the structure of the virus. This class of antibodies, called broadly neutralizing antibodies (BNAs), has been synthesized and can be injected in to humans.

Scanning electron micrograph of the HIV-1 virus, colored green, budding from cultured lymphocyte, via Creative Commons

Scanning electron micrograph of the HIV-1 virus, colored green, budding from cultured lymphocyte, via Creative Commons

There has been an initial trial of BNAs in humans. A dose of BNA was injected intravenously into volunteers. Those who had HIV showed a significant decrease in viral load, usually within a week after the injection. Their viral loads gradually started to increase as the infused antibody deteriorated over time. If this result is duplicated in other trials, it may mean that HIV can be suppressed with an IV injection every few months. Possibly freeing HIV patients from daily medications.

Data from these trials could also lead the way for the development of an anti-HIV vaccine. Researchers may find a way to get the immune system of an uninfected person to start producing BNAs that would then protect them from acquiring HIV. Again, not a cure by itself. But read on to see another strategy that might be combined with this for a possible cure:

Kick and Kill.

One of the problems in treating HIV is the fact that the virus establishes reservoirs in certain populations of cells. As I mentioned above, the virus in these cells can act to reseed the bloodstream with HIV episodically and thereby prevent antiretrovirals and the body’s immune system from removing all of the HIV allowing for a resultant cure.

The concept of “kick and kill” refers to targeting the cells that still harbor HIV. Depending on the study and drug(s) used, researchers will target the cells that host the resting HIV, attempting to either totally destroy all of the infected cells, cause them to eject all of their protected HIV or some combination of both.

In one technique, some of the individual patients’ specific HIV RNA is harvested. That RNA is then given to dendritic cells. These cells are then used to stimulate the production of T cells that are even more efficient than the patient’s own active T cells, as they are better at locating infected cells and destroying them. As those infected cells are destroyed, the HIV is released and can be cleared from the blood.

Another method uses a drug that acts to cause the cells infected with HIV to externalize the virus. The end result is that most of the cells survive now without having any remaining HIV.

Dr. David Margolis is trying a different approach. He’s using a class of drugs known as histone deacetylace inhibitors (HDACs).
One member of this class, vorinostat, when applied to HIV-infected reservoir cells, causes the HIV to reanimate, replicate and burst out of the cells. The idea is that patients given vorinostat could have a massive release of all of their hidden HIV at the same time. If those patients are also given BNAs and are taking antiretrovirals, all of the patient’s HIV would, in theory, be expressed from cells, neutralized and cleared. Thus resulting in a cure.

Of course, all of the above are still in various stages of development. Only two have made it into FDA clinical trials as yet. A lot of work still needs to be done on all of these possible therapies. That will take a few more years, at least. But all of these are interesting possibilities for treatments and, possibly a potential cure, showing how creative researchers can be when facing such a challenging problem as HIV.

Mark Thoma, MD, is a physician who did his residency in internal medicine. Mark has a long history of social activism, and was an early technogeek, and science junkie, after evolving through his nerd phase. Favorite quote: “The most exciting phrase to hear in science... is not 'Eureka!' (I found it!) but 'That's funny.'” - Isaac Asimov

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