The result, but preliminary
Is the "Sao Paulo patient" really cured of HIV?
Vera Mukhina, N+1
A new milestone is being planned in the fight against HIV infection - at the AIDS 2020 conference, they told about another person who was supposedly cured of HIV. After falling ill in 2012, he started with standard antiretroviral therapy, in 2015 he took part in trials of a new drug combination, and after three more years of standard therapy, he stopped treatment - no signs of HIV were found in his blood. 66 weeks later, the result remained the same. Doctors hope that they have finally picked up a combination of drugs that can completely cure HIV. Nevertheless, many (including the researchers themselves) believe that it is too early to rejoice – the results are preliminary, and at any moment the "Sao Paulo patient" may relapse.
To date, only two people have been reliably cured of HIV, the so–called "Berlin" and "London" patients. Another one – the "Dusseldorf patient" – has been in remission for 17 months and is considered a good candidate for the title of the third recovered.
In all these cases, doctors used the same technology – bone marrow transplantation from a donor with a mutation in the CCR5 gene. The CCR5 receptor is needed by the virus to penetrate the cells of the immune system, and the mutation complicates this process and makes the carrier resistant to infection. Such radical treatment is not safe at all and can be used only in some cases. The indication for a complete "reset" of the immune system, which, in fact, is a bone marrow transplant, can be lymphoma. The patient is "uninstalled" his personal immune system along with cancer cells and instead of it, bone marrow stem cells of the donor are implanted, from which myeloid and B cells are restored.
For transplantation, it is necessary to select a donor very carefully: he must have the necessary and relatively rare mutation in CCR5, be histocompatible and not suffer from anything dangerous for the recipient. Even if these rules are followed, transplantation remains a risky procedure – much more dangerous than conventional antiretroviral therapy – and can end in failure. So, in two patients from Boston, after they underwent transplantation and stopped taking antiretroviral drugs, HIV reappeared in the body after 12 and 32 weeks, respectively. In addition, the CCR5 mutation only works with a certain type of HIV and does not help with the rest.
The new case is fundamentally different from all of the above in that the "Sao Paulo patient" did not have blood cancer and bone marrow transplantation was not done to him. Instead, he and four other volunteers received a particularly aggressive cocktail of medications. In addition to the three drugs they were already taking by that time (Tenofovir, Emtricitabine and Efavirenz, which block viral reverse transcriptase in different ways), it included two more drugs - dolutegravir and maraviroc. The first prevents the viral sequence from embedding into the human genome, and the second binds to CCR5 and prevents HIV from entering the cell. According to the idea of the researchers, such a combination – by analogy with the complex intake of antibiotics – was supposed to help impose the pathogen from all sides and prevent it from escaping.
On top of this, patients were prescribed nicotinamide (or vitamin B3), which in theory has an immunomodulatory effect. At the end of June, the Brazilian Journal of Infectious Diseases published an article by a Brazilian-American team of authors in which they demonstrated the ability of this substance to activate HIV ex vivo, holed up in long-lived memory T cells.
The HIV cycle
HIV uses RNA as a carrier of information.
When a virus enters a cell, the cellular machinery synthesizes enzymes with its RNA, with the help of which viral DNA is synthesized on the cell RNA matrix and embedded in the cell genome. There, the usual synthesis of RNA and proteins begins with it, which are packed into ready-made virions and leave the cell.
Even if the HIV activity is completely blocked with the help of antiretroviral therapy, the "silent" DNA embedded in the genome will still remain, and after stopping taking medications, the virus will activate again and begin to multiply again.
The virus can be in such a depressed state for years and neither the immune system nor medications are able to detect and destroy it.
HIV Life Cycle (Sirozha / wikimedia commons / CC BY-SA 4.0).
As in the case of other known activators, the effect of nicotinamide is tied to epigenetics – in order to "turn on" the virus, you need to make the DNA packaging in the area of virus integration not so dense by removing the "silent" DNA tags from DNA and histones and marking it as active. One of the characteristic labels of active DNA is acetylated histones. To make DNA "silent", acetylation is removed using the enzyme deacetylase. Nicotinamide is also needed to work as an inhibitor of this acetyltransferase, which allows you to activate immune cells and make them synthesize HIV RNA and proteins. Interestingly, acetyltransferase inhibition also works in the case of some cancers, making them more immunogenic.
As a result of taking such a strong cocktail of drugs from one of the volunteers from the experiment in Brazil – we don't know anything about the other four yet – the HIV level dropped to a minimum, and after 48 weeks this patient returned to his standard therapy, and after a few years stopped taking antiretroviral drugs altogether – the virus was not detected in his blood. It is not detected even 16 months later, and this gives hope that the virus has been completely eradicated.
Despite this, the scientists themselves and other experts emphasize that these are only preliminary results that still need to be rechecked. 16 months is not enough to unambiguously determine whether HIV has been completely eliminated. In this regard, the story of the "Mississippi child" is indicative. This girl has been receiving antiretroviral therapy since birth, a month later the HIV level in her blood dropped below detectable. After a while, she stopped taking medications: the virus was still impossible to detect, but two years after the cancellation, it reappeared in large quantities.
To show that HIV had completely disappeared from the organisms of the "Berlin" and "London" patients, they were given additional tests that showed the absence of the virus not only in the blood, but also in other potential reservoirs, such as lymph nodes and intestines, in which a couple of sick cells could accidentally get lost. The "Sao Paulo patient" is just about to undergo these tests - they were postponed due to the COVID–19 epidemic - and we will find out their results later.
Scientists are also cautiously optimistic about the selected combination of drugs – so far it has worked (if so) only on one person, and it is not at all necessary that the same thing will happen with any other. According to the director of DAIDS Karl Dieffenbach, this effect may well be due not at all to the action of nicotinamide or any other component, but to the genetic and/or immunological characteristics of a person – and this is the first thing worth checking in the future.
An important role in the case of the "Sao Paulo patient" could also be played by the speed with which therapy began. As in many other cases, the exact time of infection of the patient is unknown, but he himself assumes that it happened just a few months before he found out about his status and started taking medications. If so, since he had few infected cells, there were more chances to expel HIV from them than those whose therapy started later.
In any case, in order to recommend treatment with nicotinamide or the whole combination of drugs, it will be necessary to conduct many more tests, and most importantly – to show its effectiveness on a much larger number of patients and confirm its safety. Otherwise, it may turn out to be just as pointless as treating COVID-19 with hydroxychloroquinine, which was so much hoped for at the beginning of the epidemic.
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