A little more than twenty years ago, two developments occurred around the same time that tremendously advanced our ability to treat and manage HIV infection. First, we finally had powerful combinations of drugs that could suppress the HIV virus, primarily a class known as the protease inhibitors (drugs like Viracept, Kaletra, Reyataz and Prezista). Around the same time, we had validated that the viral load, a test that tells how much HIV was in the blood, was a good way to measure how active the infection was and how effectively the drugs were working. Combining these two advancements, we were able to show that these powerful drug combinations could totally suppress the activity of the virus in the blood undetectable viral load.
This was fantastic because with an undetectable viral load from these drug combinations the immune system would improve and would be protected. So, if there is no more virus detected in the blood, that person is cured right? That’s what we were hoping. Unfortunately, whenever we would stop treatment in someone who had been undetectable, the virus would soon reappear in the blood! How could it be undetectable and then suddenly reappear after stopping the medicine? Where was this virus coming from, if the person had been undetectable??
As you know, the HIV virus targets the CD4+ cell, a type of T-lymphocyte. The T-lymphocytes are the special infection-fighting white blood cells. Normally, HIV virus infects cells, turns them into a factory to make more viruses and then, the new viruses are released to spread the infection. The infected lymphocytes die, which is why the immune system becomes damaged as more of the protective cells are killed off by the virus. But something else interesting happens.
Some of the infected lymphocytes don’t die. After infection, these cells start to quiet down and then become dormant. They are not active and it’s almost as if they are hibernating. The HIV virus is unable to replicate when the cells are in this dormant state. Also, because the virus can’t replicate, the medicines that suppress HIV aren’t able to work well in these particular lymphocytes. The ability of these lymphocytes to go into a dormant state is an important feature of the immune system.
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They can remain in thisdormant state for years and they appear to hide out in parts of our body that still are partly a mystery. These resting T-lymphocytes normally stay in this quiet state until some signal from the immune system stimulates them to wake up and become active. When they become active, they then start to produce HIV virus that has remained quiet. These resting lymphocytes that are infected with HIV but not producing the virus are what we refer to as a cellular reservoir.
Now, if these resting lymphocytes comprising the reservoir become active while the person is taking HIV medicines, the medicines are able to work and suppress the virus. They remain undetectable and it is no big deal. But if a person is undetectable and stops taking medicine, some of these resting cells may wake up and start making new virus and soon there is virus detected in the person’s blood. These infected resting lymphocytes are the source of the virus that rebounds in the blood when an undetectable person stops taking medicine.
So how are scientists dealing with this? First, recall from the previous article that there are people whose immune systems can control the virus on their own (Elite controllers) and also, there are some people who can control the infection after being suppressed on the medicines for a while (Post-treatment controllers). However, these special categories do not represent the vast majority of folk who are infected. Most people will experience a rebound of the virus in the blood if they stop taking their medicines after being suppressed.
So scientists realized that we must somehow stop these resting lymphocytes from being activated and producing virus if we are to have any hope of curing this infection. Even though these resting lymphocytes may be hiding in parts of the body that haven’t been identified yet, we do have some specialized tests that can estimate how big this reservoir is, or how many of these infected resting lymphocytes a person has. In studies where patients were able to control their HIV infection without medicine after successful treatment (post-treatment controllers), having a smaller reservoir was one of the most important factors.
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Researchers have developed two main strategies to deal with these lymphocytes. The first approach is called “Kick and kill”. In this approach, we use drugs that are designed to stimulate these resting cells all at the same time, wherever they are hiding in the body. This is done while the patients are taking HIV medicines. Once they become active and start making virus, then either the HIV medicines can get in the cells and shut down virus production or the immune system is now able to recognize these infected cells and kill them. If we are successful inforcing virus out of the reservoir or eliminating it, then when a person stops taking their medicine, there should be no rebound of virus because it will all be gone. Cure!!
The other approach used to target these cells is called “Block and lock”. In this approach, an experimental drug blocks the ability of the virus to replicate, after infected resting cells become activated. When this experimental drug is combined with regular HIV medicines, there has been no rebound in virus in the blood after the drugs are stopped; at least in research animals.
Ultimately, whether we are successful in eliminating the reservoir by forcing all the virus out and eliminating it, or by locking the virus in, the existence of the reservoir is a major barrier to curing this infection. Lots of research currently is focused on dealing with the reservoir to achieve a cure. We’re not there yet, but each study that fails gives us clues that can lead to success. Fingers crossed.
Dr. Crawford has over 25 years of experience in the treatment of HIV. While at Howard University School of Medicine, he worked in two HIV-specialty clinics at Howard University Hospital. He then did clinical research as a visiting scientist with the AIDS Clinical Trials Group (ACTG) at Johns Hopkins University School of Medicine. He served as the Assistant Chief of Public Health Research with the Military HIV Research Program where he managed research studies under the President’s Emergency Plan for AID Relief (PEPFAR) in four African countries.
He is currently working in the Division of AIDS in the National Institutes of Health. He has published research in the leading infectious diseases journals and serves on the Editorial Board of the journal AIDS. Any views and perspectives in his articles on blackdoctor.org are not representative of any agency or organization but a reflection of his personal views.
