The two days of the Symposium in search of a cure for HIV / AIDS they became a fixture before the conferences and last week's meeting at the International AIDS Society Conference in Vancouver highlighting a wider range of experimental approaches than ever before in finding ways to eliminate HIV infection from the body.
Daniel Kuritzkes Harvard Medical School, in its inaugural lecture, told delegates that, to some extent, the proliferation of different approaches was due to the beginning of disillusions for healing. We still have only one person, Timothy Ray Brown (the Berlin Patient) who has been cured of HIV; six other cancer patients in whom the same type of stem cell transplant therapy had been tried died - a reminder that such a demanding procedure, such as a bone marrow transplant, will never be an approach that can be used in one general way.
The main approach to healing that researchers are working on is still the strategy called "kick and kill". It uses immune stimulants to induce the cells in which the latent HIV hides - the so-called reservoir cells - to come out of their hiding places. The hope is, then, that its activation alone will lead HIV to its death by exhaustion, through the natural immune response; if not, the goal is to make these cells the target of drugs that kill them. Without eliminating this reservoir, a small minority of cells capable of spitting out new copies of HIV will remain in the body and experiments have shown that HIV can reappear even when not detectable with viral load in the most sensitive tests, as in the case of drinks Mississippi.
Since the kick and kill strategy gained great importance, there were also disappointments: the experimental design of the agents used to reverse the so-called viral “latency” certainly stimulated virus production by the cells - but without resulting in any decrease in the size of the viral reservoir . This appears to be due to the drug chosen - such as panobinostat HDAC inhibitors or Romidepsin - there are other unforeseen events and immunological effects, including suppressing the activity of CD8 cells that can be fundamental to “kill”, something that is part of the process.
However, Kuritzkes said for the moment “Inversion of latency is a necessary condition, if not a sufficient condition for reducing the reservoir of cells infected by HIV.” Kuritzkes told AIDSMAP: “Most interventions that are likely to kill infected cells require the virus to be visible to the immune system. The alternative idea, which permanently suppresses viral production in reservoir cells ”-- - as in the study published last week on the inhibitor of a Tat "at the moment they seem to involve a latency-suppressing pill every day instead of antiretroviral therapy. This is not really a cure. ”
Another cure research has involved investigating immune responses both in spontaneous elite HIV controllers - who maintain low viral loads and high CD4 counts when their infection begins - and so-called “post-treatment controllers”, such as members of Cohort viscont, who start HIV therapy early but then manage viral control for long periods without treatment. These cases are fascinating for researchers, they imitate the “functional cure” of HIV, which is one of the research objectives for the cure. A healing symposium heard of another case, this time of a young woman now 18 years old who has kept viral load under control for the past twelve years.
By definition, however, most people with HIV cannot become post-treatment controllers since, in general, controllers are people who start treatment very early, and even then, they will probably have to develop a specific immune response to HIV, something possibly easier to induce with the preventive vaccine than with post-infection treatments.
For these reasons, while the symposium included presentations on romidepsin and other drugs aimed at reversing latency like ingenol - a relative of the prostratin latency reverser - there was more excitement about the drugs that were intended to prevent cells from becoming quiescent (dormant) and never enter the latency phase.
Which implies inhibiting the activity of latency promoters, such as cellular protein PD 1, which cuts off activated T cells, making them invisible to the immune system. PD-1 is not the only latency promoter, and Colleen McGary of Emory University has proposed using drugs that block PD-1 and another latency promoter called CTLA-4 (CD152) to prevent latency, since cells that express both the recipients are much more efficient at incorporating HIV RNA than those expressing one or none of the receptors. A CTLA-4 blocker, ipilimumab, is already being used for melanoma. However, PD-1, in particular, is a protein ubiquitous in the immune system and drugs that block its activity have proven to be quite toxic when used in cancer research.
- Another goal is a cellular protein called SAMHDI, which is already the target of an anti-leukemia drug called dasatinib. Jose Alaci of the Salud Carlos III Institute of Spain told the congress that SAMDHI reduces cell division and, in T-cells, reduces their ability to produce new viruses; however, it usually works only during a small part of the immune cycle and then it is phosphorylated, or becomes inert.[Translator's note: I searched for the phosphorylated entry and found the following definition: Phosphorylate is to add a phosphate group to a protein resulting in an important regulatory mechanism, enabling or disabling a biological function] Dasatinib disrupts this phosphorylation and maintains SAMHDI activity, which means that it prevents viral transcription from happening inside the cell, suggesting that it may act as a reverse transcriptase inhibitor, but it acts on the cellular response against HIV .
Harvesting cells infected with antibodies ...
As well as preventing cells from entering latency, we also need a better way for the immune system to recognize and kill the reservoir cells of people infected with HIV who are forced out of hiding. Only a small minority of reservoir cells never wake up and begin to produce all the replication of viruses capable of what are called “reactivation events”. A poster at the symposium on healing researchers at the University of New South Wales is estimated to have an average “reactivation event” in infected HIV reservoir cells every 5 to 8 days, although under effective antiretroviral therapy they never become an event that generates “true infection” that results in “detectable viremia”. Each reactivation event is literally initiated and terminated by a single cell, the researchers told AIDSMAP that the average period of time that an individual CELLULAR reservoir remains quiescent before it has a 50% chance of reactivation is approximately 17.000 years.
Marcus Altfeld of Harvard Medical School gave an interesting presentation in which he described the different stages of HIV reproduction, which recently stimulated reservoir cells. As mentioned, full-fledged activation is quite rare. The cells may actually be sending viral particles oriented towards passive immunization with the use of monoclonal antibodies, and John Mascola of the US National Institute of Health said that antibodies that treat skin cancer had already been designed to have a blood half-life for more than more than 6 months.
That would not be a cure for the HIV virus, of course. To maintain the levels of antibodies in the blood that are needed for a therapeutic vaccine to stimulate the production of neutralizing antibodies, and the problem with antibodies to HIV is that they have always been specific to just a single strain of the virus. Mascola said that most of the largely neutralizing antibodies were now able to destroy 90% of viral strains or to mark cells for destruction than to do so. While 10% of the strains that escaped would be sufficient to "reverse the cure", he described the development of the new "bispecific" antibodies [translator's note: the closest I could come up with this term was “bi-specific and I didn't find the word outside the scientific context and, to be more objective, I only found it within the sites that reference this text. Stay bi-specific until I can find something that can replace it; however, the continuity of the text seems to legitimize the expression] that can combine 2, each with 90% neutralization capacity, into one molecule, or can combine a viral neutralizer with a neutralizing antibody that attracts CD8 cells to come and attack the infected cell, destroying it and, with it, the virus .
… And with CD8 cells…
Most reservoir cells produce viral proteins or viral RNA sequences without ever generating the complete assembly of the virus. They do, however, exhibit "epitopes" or small extracts of viral proteins on their surface that act as distress alerts to attract CD8 cells that destroy infected cells. Again, the problem with HIV CD8 cell responses, such as the antibody response, is that the virus can mutate and evade its action. But highly repressive broad-spectrum therapeutic vaccines after ART (Antiretroviral Therapy) have driven the viral load down as far as possible, and it is to be expected, and prepared to detect cell reactivation events so efficient that they would be caught before the HIV could have a chance to escape immune surveillance.
Sarah Fidler of the UK healing research consortium CHERUB described a study in which two other CD8-inducing vaccines are given in the 24th and 32nd weeks after starting ART. Another vaccine that could be useful in this context is the cytomegalovirus-based vaccine, CMV, which has caused quite a stir in the past year with its apparent ability to bring about a functional cure or even complete cure in monkeys.Phase 1 tests are ongoing in humans.
Another way to prevent the virus from escaping immunological surveillance is to cause an immune reaction to those parts of the virus that are highly "conserved" - the parts that the virus cannot mutate without the virus mutilating. In HIV these areas are usually kept well hidden "out of sight" of the immune system. When HIV binds to the CD4 molecule in cells, however, the gp160 protein that does the job of binding to CD4 has to change shape to expose a highly conserved part of the gp41 fusion protein for a very short time. The broadly neutralizing antibodies, "the tips" can reach and attach to this preserved area; in the early days of AIDS, soluble CD4 proteins were used, experimentally, in an attempt to force this conformational change in gp160. Andres Finzi of McGill University described a new small CD4 analog molecule called JP-III-48 that, unlike soluble CD4, could be an oral pill. With the congestion, the gp160 molecule would be opened and the conserved stretches would be exposed to the CD8 cells to patrol and, thus, to reduce the size of the reservoir.
… And with “Natural Killers” cells
One of the most difficult challenges of cure research is to find ways to direct the immune system's attention to cells quickly, from the initial stage of a reactivation event. At this point they are beginning to transcribe pro-viral DNA integrated into pieces of RNA that are cut or spliced. These spliced RNA particles will then serve as models for individual viral components. People with cells that contain large amounts of undivided HIV RNA are less likely to experience reactivation events than people whose cells contain spliced DNA parts. As the Tat protein is absolutely essential in the process that splices the DNA of HIV that last week's announcement of a small molecule inhibiting the Tat protein was particularly interesting.
However, this is not the only HIV virus protein that could be designed to prevent reservoir cells from going beyond this stage. The cells begin to produce RNA exhibit "stress proteins" on their surface, which, while not clearly external and therefore attracts a cellular immune response, also attracts the attention of the innate immune system - the evolutionarily oldest , less selective, but with a stronger and faster immune response.
These stress proteins bind to a cell receptor called NKG2D, which is presented by natural killer cells, the shock troops of the innate immune system. HIV, however, has a protein called nef, whose job is to suppress the expression of stress proteins that attract natural killer cells. A small molecule that inhibits Nef, or an anti-NEF vaccine, can block the activity of the neph, increasing the expression of cellular stress proteins, and generate an innate immune response capable of attacking cells in the reservoir at a very early stage of activity.
We try to make cells immune to HIV
Finally, there is the option of using gene therapy to try to repopulate the immune system with cells that lack HIV (s) the necessary receptor (s) for replication - in particular the CCR5 receptor used by most transmitted viruses. This was the basis of Timothy Brown's cure: his new set of bone marrow cells came from a donor who, of course, lacked the CCR5 receptor. Note, again, that six attempts were made to repeat the process and all led to death.
The approaches using the individual's own CD4 cells that have their CCR5 receptor genes removed and are then reinfused into the patient, without going through the drastic step of erasing their entire immune system in the first place and were among the first healing experiments performed on humans. Matt Sharp, was one of the first volunteers in this study about the cure and this [study] has been described as the one with the most lasting benefits - few side effects, and a long drive in the development of CD4 cells.
One of the problems with the exclusion of the CCR5 receptor in immune cells is that HIV can use another CXCR4 receptor, and in fact viruses that use CXCR4- receptors have appeared in at least one of the failed experiments that tried to replicate Tim Brown's cure. , the Berlin patient. Unfortunately, while people without CCR5 can remain in good health, CXCR4 is a much more essential part of the immune system, and CXCR4 blockers used as treatments for HIV have failed due to unacceptable toxicity.
However, a team from the University of Pennsylvania has cell-engineered CD4 cells to carry a “fused peptide” on their surface, which is like a necklace, a combination of part of HIV's gp41 fusion protein with CXCR4 receptors. or CCR5 receivers. Cells that express this fused peptide are as if they lacked CCR5 receptors and / or CXCR4 receptors and are therefore resistant to HIV infection.
Maintaining the cure of HIV as a priority
This is just a small sample of the numerous cure strategies and drug targets explored during the 2nd day of the Healing Workshop. There are two other therapeutic vaccines being tried on monkeys, and both are promising in the field of immune responses. There are also many experiments on microbes in cell induction dealing with cellular vulnerability to infection and studies on latency. Several other promising drug and vaccine targets have been described.
What was missing this year would be a single significant breakthrough or an orientation towards research for healing: Research on healing is at the stage of leading to very promising facts, but it lacks a strong signal that indicates that a variety of strategies, there was one in pursuit of healing. In all likelihood, as Marcus Altfeld recalled at the beginning of the symposium, we have a combination of approaches. Sharp told Congress that now was not "the time to rush a decision on any individual healing approach."
He added that it was essential to include research for a cure in any discussion of the term AIDS. He was concerned, and he said it, that recent conversations about access to treatment, treatment like pre-exposure prevention and prophylaxis (PrEP), and not mentioning objectives as 90-90-90.
Curing HIV is what he doesn't want to see off the agenda, or off the funders' priority list. While reducing the incidence of HIV in places as diverse as San Francisco and Botswana is welcome, Sharp adds: only cure, as well as HIV treatment and prevention is what can really bring an end to the epidemic.
"How can we end the AIDS epidemic without a cure?" He asked.
Written by Gus Cairns in a joint action of AIDSMAP and HIV & Hepatites.Com was published in Published on Friday, July 31, 2015
Translated from the original in English: IAS 2015: Targets Proliferate in HIV Cure Research By Cláudio Souza and Revised by Mara Macedo in August 05 2015
Towards HIV Cure 2015 and Symposium. Vancouver, July 18-19, 2015.
Presentations are available at www.iasociety.org/What-we-do/Towards-an-HIV-Cure/Events/2015-Symposium. The symposium program is available atwww.iasociety.org/Web/WebContent/File/HIV_Cure_Symposium_Programme_2015.pdf
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