The two days of Symposium in search of a cure for HIV / AIDS have become a fixture before the conferences and last week's meeting at the International AIDS Society Conference in Vancouver highlighting the more varied range of experimental approaches than ever before in finding ways to eliminate HIV infection from the body.
Daniel Kuritzkes of Harvard Medical School, in his inaugural address, told delegates that, to a certain extent, the proliferation of different approaches was due to the onset of delusions for healing. We still have only one person, Timothy Ray Brown (the Berlin Patient) who was 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 from a in general terms.
The main approach to healing that researchers are working on is still the so-called "kick and kill" strategy. It uses immune stimulants to induce cells in which latent HIV lurks - so-called reservoir cells - out of their hiding places. The hope, then, is that its activation alone will bring HIV to its death by exhaustion through the natural immune response; if it is not, the goal is to make these target drug cells 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 may reappear even when undetectable 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 viral reservoir size . This appears to be due to the chosen drug - as HDAC inhibitors panobinostat or Romidepsin - there are other unforeseen and immunological effects, including greatly suppressing the activity CD8 cells that may be fundamental to "kill", something that is part of the process.
However, Kuritzkes said for the moment "Reversal of latency is necessary, if not sufficient condition to reduce the reservoir of HIV-infected cells." Said Kuritzkes to aidsmap: "Most of the interventions that are likely to eliminate infected cells require the virus to be visible to the system immune. The alternative idea, which suppresses viral production permanently in reservoir cells "-- - as in the study published last week on the inhibitor of Tat “at the moment they seem to involve a pill suppressing latency every day instead of antiretroviral therapy. This is not really a cure. "
Another healing research has involved investigating immune responses in both the spontaneous elite spontaneous HIV controllers - who maintains low viral loads and high CD4 counts when they form the onset of their infection - and so-called "post-treatment controllers," such as limbs of Cohort viscont, who initiate HIV therapy early but then manage viral control for long periods without treatment. These cases are fascinating to researchers, they mimic the "functional cure" of HIV, which is one of the research goals for healing. A symposium on healing heard in another case, this time of a young woman now with 18 years that has maintained viral load under control for the last twelve years.
By definition, however, most people with HIV can not become aftertreatment controller since, in general, the drivers are persons who initiate treatment early, and even so would probably have to develop a specific immune response to HIV possibly somewhat easier to induce preventive vaccine than with post-infection treatments.
For these reasons, while the symposium included presentations on romidepsin and other drugs aimed at reversing latency as ingenol - a relative of the reversal latency prostratin - there was more excitement about drugs that had the goal of preventing cells from becoming quiescent (dormant) and never enter the latency phase.
This implies inhibiting the activity of the latency promoters, such as the cellular protein PD 1, which cuts the 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 expressing both the receptors are much more efficient in the sense of incorporating HIV RNA relative to 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 ubiquitous protein in the immune system and drugs that block its activity have proven quite toxic when used in cancer research.
- Another goal is a cellular protein called SAMHDI, which is already targeted by an anti-leukemia drug called dasatinib. Jose Alaci of the Carlos III Health Institute of Spain told Congress that SAMDHI reduces cell division and, in T-cells, reduces their ability to produce new viruses; however, it usually only works for a small part of the immune cycle, and then is phosphorylated, or becomes inert.[Note from the translator: 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 by activating or deactivating a biological function] Dasatinib disrupts this phosphorylation and maintains the activity of SAMHDI, which means that it prevents viral transcription from happening inside the cell, which suggests that it may act as a reverse transcriptase inhibitor, but this 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 virus replication capable of what are called "reactivation events." A poster at the Symposium of Cure Researchers at the University of New South Wales estimated that there is on average a "reactivation event" in the reservoir cells of HIV infected every 5 to 8 days, although under effective antiretroviral therapy these never become a "true infection" event that results in "detectable viraemia." Each reactivation event is literally started 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 50% chance of reactivation is approximately 17.000 years.
Marcus Altfeld of Harvard Medical School made an interesting presentation in which he described the different stages of reproduction of HIV, which newly stimulated reservoir cells. As mentioned, full right activation is quite rare. The cells may actually be sending passive immunization-oriented virus particles with the use of monoclonal antibodies, and John Mascola of the US National Institutes of Health said that antibodies that treat skin cancer had already been designed to have a half-life in the blood for more than 6 months.
This would not be a cure against HIV virus, of course. To maintain antibody levels in the blood required for a therapeutic vaccine stimulates the production of neutralizing antibodies, and the problem with HIV antibodies is that they have always been specific to only one virus strain. Mascola said that most broadly neutralizing antibodies were now capable of destroying 90% of viral strains or mark cells for destruction than do it. At the same time 10% of the strains that escape would be enough to "reverse the cure," he described the development of new antibodies "bispecific" [Translator's note: the closest I could come up with this term was "bi-specific and did not find the word out of the scientific context and to be more objective, only found within the sites that reference this entry. It is as specific bi until I can find something to replace him; however, the continuity of the text seems to legitimize the expression] that can match 2, each with 90% neutralization capacity, in a one molecule, or can combine a viral neutralizing 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, 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 CD8 cell responses by HIV, such as the antibody response, is that the virus may undergo mutations to evade it. But highly repressive broad-spectrum therapeutic vaccines after ART (Antiretroviral Therapy) have conducted the viral load down as much as possible, and hopefully, and have been prepared to detect events of cellular reactivation so efficient that they would be captured before HIV might have a chance of escaping immune surveillance.
Sarah Fidler of the UK Healing Research Consortium CHERUB described a study in which two other CD8-inducing vaccines are given at 24 and 32 weeks after the initiation of ART. Another vaccine that could be useful in this context is the cytomegalovirus (CMV) -based vaccine that caused a major upheaval in the last year with its apparent ability to bring about a functional cure or even complete cure in monkeys.Phase 1 tests are underway in humans.
Another way to prevent the virus from escaping from immune surveillance is to elicit an immune response to those parts of the virus that are highly "conserved" - the pieces that the virus can not 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 CD4 molecule in cells, however, the gp160 protein doing the binding work on CD4 must change shape to expose a highly conserved part of the gp41 fusion protein for a very short time. Widely neutralizing antibodies, "the tips" may arrive and attach to this preserved area; in the early days of AIDS, soluble CD4 proteins were experimentally used in an attempt to force this conformational change of gp160. Andres Finzi of McGill University described a new small molecule CD4 analogue called JP-III-48 which, unlike soluble CD4, could be an oral pill. Congestion would open the gp160 molecule and expose the conserved passages to the CD8 patrol cells and thereby decrease the size of the reservoir.
... And with cells "Natural Killers"
One of the most challenging challenges of curing research is finding ways to direct the attention of the immune system to cells quickly, from the initial phase 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 the individual viral component templates. People with cells that contain large amounts of undivided HIV RNA are less likely to undergo reactivation events than people whose cells contain spliced DNA parts. As Tat protein is absolutely essential in the process that the DNA splice of HIV that the announcement last week of a small molecule inhibitor of the Tat protein was particularly interesting.
However, this is not the only HIV virus protein that could be intended to prevent reservoir cells from exceeding this stage. Cells begin to produce RNA exhibit "stress proteins" on their surface, which, while not clearly external and therefore attracting a cellular immune response, also attracts the attention of the innate immune system - the evolutionarily older , less selective, but with a stronger and faster immune response.
These stress proteins bind to a cellular receptor called NKG2D, which is presented by natural killer cells, shock troops of the innate immune system. HIV, however, has a protein called nef, whose one of its attributes is to suppress the expression of stress proteins that attract natural killer cells. A small Nef inhibitor molecule, or an anti-NEF vaccine, can block nef activity by increasing the expression of cellular stress proteins, and generate an innate immune response capable of attacking the cells of the reservoir at a very early stage of activity.
Wanted to the immune cells of HIV
Finally, there is the option to use gene therapy to attempt to repopulate the immune system with cells that lack (s) the HIV (s) receptore (s) need (s) for replication -in particular receptor used by most CCR5 the transmitted virus. This was the basis of Timothy Brown's healing: his new set of bone marrow cells came from a donor to which lacked naturally CCR5 the receiver. 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 the genes their CCR5 receptor 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 in humans. Matt Sharp, was one of the first volunteers in this study on cure and this [study] was described as having the most lasting benefits - few side effects, and a long push in the development of CD4 cells.
One of the problems with the exclusion of CCR5 receptor on immune cells is that HIV can use other CXCR4 receiver, and indeed viruses that use CXCR4- receivers have appeared in at least one of the failed experiments that tried to reproduce the healing Tim Brown the Berlin patient. Unfortunately, while people without CCR5 may remain in good health, CXCR4 is much more essential part of the immune system, and CXCR4 blockers used as treatments for HIV failed due to unacceptable toxicity.
However, a team from the University of Pennsylvania was engineered into CD4 cells that loaded onto their surface a "fused peptide," which is like a paste, a combination of part of the HIV gp41 fusion protein with the CXCR4 receptors or CCR5 receptors. Cells expressing this fused peptide are as if they lack the CCR5 receptors and / or CXCR4 receptors and thus are resistant to HIV infection.
Maintaining the cure of HIV as a priority
This is just a small sample of the numerous healing strategies and drug targets explored during the 2 day of the Healing Workshop. There are two other therapeutic vaccines being tested in monkeys, and both are promising in the field of immune responses. There are also many experiments in microbes in cell induction addressing cellular vulnerability to infection and latency studies. Several other targets on promising drugs and vaccines have been described.
What was missing this year would be a single significant advance or conducting research for the cure: The search of the cure is in the phase lead to very promising facts, but lacks a strong signal to indicate that a variety of strategies, there was one in pursuit of healing. In all probability, as Marcus Altfeld recalled earlier this symposium, we have a combination of approaches. Sharp told Congress that now was "not the time to rush a decision on any single approach to healing."
He added that it was essential to include research for cure in any discussion of the term AIDS. He was concerned, and he said so, that recent talks about access to treatment, treatment such as prevention and pre-exposure prophylaxis (PrEP), and the lack of mention objectives as 90-90-90.
Curing HIV is what he does not want to see get off the agenda, or go off the list of funders' priorities. While reducing the incidence of HIV in places as diverse as San Francisco and Botswana are welcome, Sharp adds: only cure as well as HIV treatment and prevention is what really can 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 day
Translated from the original English: IAS 2015: Targets Proliferate in HIV Cure Research By Claudio 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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