The two-day Symposium in search of a cure for HIV / AIDSThey became a fixture before the conference and last week's meeting at the International AIDS Society Conference in Vancouver highlighting the widest range of experimental approaches than ever in finding ways to eliminate HIV infection in the body.
Daniel Kuritzkes of Harvard Medical School, in his inaugural lecture, he told delegates that to a certain extent, the proliferation of different approaches was due to the start of disappointments for healing. We still have only one person,Timothy Ray Brown (the Berlin Patient)who was cured of HIV; Six other patients with cancer in which the same type of stem cell transplant therapy was tried died - a reminder that such a demanding procedure, as is a bone marrow transplant, will never be an approach that can be used in a general.
The main approach to healing that researchers are working is still the strategy called "kick and kill." This uses immune stimulants to induce cells in the latent HIV hides - the so-called reservoir-cells - to come out of hiding. The hope is then that their activation by itself, bring HIV to their death by exhaustion through the natural immune response; if not, the goal is to make these target cells to drugs that kill. Without eliminating this reservoir, a small minority of cells able to spit out new copies of HIV remain in the body and experiments have shown that HIV can recur even when not detectable with the most sensitive viral load tests, as in the case ofdrinks Mississippi.
Since the kick and killing strategy was very important, there was also disappointments: the experimental design of agents used to reverse the so-called "latency" viral certainly stimulated virus production by the cells - but without resulting in any reduction in the size of the viral reservoir . This seems to be due to drug of choice - as HDAC inhibitors or panobinostatRomidepsin- There are other unforeseen and immunological effects, including suppressing the very CD8 cell activity that may be critical to "kill", which 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 time that seem to involve suppressing pill latency every day instead of antiretroviral therapy. That's really not a cure. "
Another healing research has involved investigating immune responses in both spontaneous elite controller HIV - which maintains low viral loads and high CD4 counts when forming the beginning of their infection - and the so-called "post-treatment controllers" as members ofCohort viscont, Which start HIV therapy early but then manage the viral control for long periods without treatment. These cases are fascinating for researchers, they mimic the "functional cure" of HIV, which is one of the research goals for healing. A symposium on healing heard of another case, this time of a young woman now 18 years hasmaintained 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 designed to reverse the latency as ingenol - a relative of prostratin latency reverser - there was more excitement about drugs that was intended to prevent the cells become quiescent (dormant) and never enter the lag phase.
This implies latency inhibit the activity of promoters, such as cellular proteinPD 1Which cuts the activated T cells, making them invisible to the immune system. PD-1 is not the only promoter latency and Colleen McGary Emory University proposed to use drugs that block the PD-1 and another promoter latency called CTLA-4 (CD152) to avoid the latency, since cells expressing both the receivers are much more efficient to incorporate HIV RNA compared those who express one or none of the recipients. A blocking CTLA-4, ipilimumab, is already being used for melanoma. However, the PD-1, in particular, is a ubiquitous protein in the immune system and drugs that block their activity has proved 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 the Instituto de Salud Carlos III of Spain told Congress that SAMDHI reduces cell division, and T-cells, reduces the ability of same to produce new viruses; however, it usually operates only for a small part of the immune cycle and then is phosphorylated cycle or becomes inert.[Translator's note: I researched the phosphorylated entry and found the following definition: Phosphorylateis to add a phosphate group to a protein resulting in an important regulatory mechanism by activating or deactivating a biological function] Dasatinib interrupts this phosphorylation and maintains SAMHDI activity, meaning that it prevents viral transcription occurs within the cell, suggesting that it can act as a reverse transcriptase inhibitor, but it acts on the cellular response against HIV .
Harvesting cells infected with antibodies ...
And prevent cells from entering latency, we also have the need for a better way for the immune system to recognize and kill cells reservoir 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 virus replication capable of what are called "reactivation events." A poster at the symposium of researchers from healing the University of New South Wales it is estimated that there are an average "reactivation" event in HIV reservoir cells infected each 5 8 the day, while taking antiretroviral therapy effective these never generating events become one of "true infection" resulting in "detectable viremia." Each reactivation event is literally started and completed by a single cell, the researchers said the aidsmap that the average length of time that an individual MOBILE 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 recently stimulated cells reservoir. As mentioned, the full activation is quite rare. The cells may actually be sending viral particles oriented passive immunization using monoclonal antibodies, and John Mascola the US National Institutes of Health said that antibodies that treat skin cancer had been prepared so as to have a half-life in blood over 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 never generate the complete assembly of the virus. They nevertheless exhibit "epitopes" or short excerpts of viral proteins on their surface that act as the distress alerts to attract CD8 cells that destroy infected cells. Again, the problem with CD8 HIV cell responses, such as antibody response, is that the virus can be mutated to escape into his action. But therapeutic vaccines broad spectrum highly repressive after ART (Antiretroviral Therapy) has led to viral load down as much as possible, and is to be expected, and prepared to detect cell reactivation events so efficient that they would be captured before the HIV could have a chance to escape immune surveillance.
Sarah Fidler of healing research consortium of the UK CHERUBHe described a study in which two other CD8 inducing vaccines are given in 24ª and 32ª weeks after initiation of HAART. Another vaccine that could be helpful in this context is the vaccine based on cytomegalovirus, CMV, which caused quite a stir last year with its apparent ability to bring a functional cure or even complete cure in monkeys.Phase 1 tests are underway in humans.
Another way to prevent the virus escape immune surveillance is to trigger an immune reaction to the parts of viruses that are highly "conserved" - the parts that the virus can not mutate without mutilate the virus. HIV in these areas are usually kept well hidden "out of sight" of the immune system. When HIV CD4 molecule binds to the cells, however, the protein gp160 making the fixing work CD4 must change in order to expose a highly conserved part of the fusion protein gp41 for a very short time. The broadly neutralizing antibodies, "tips" can reach out and attach to this unspoilt area; in the early days of AIDS, soluble proteins CD4 been used experimentally in an attempt to force this conformational change gp160. Andres Finzi McGill University described a new small molecule analogue CD4 JP-called III-48 that, unlike soluble CD4 could be an oral pill. With congestion would gp160 molecule and open to expose the passages would be maintained for the cells patrol CD8 and thus diminish the size of the reservoir.
... And Cells "natural killers"
One of the toughest challenges of healing research is to find ways to direct the attention of the immune system to cells rapidly 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 particles of RNA spliced serve then as models of individual viral components. People with cells that contain large amounts of HIV RNA not divided are less susceptible to reactivation events than those whose cells contain DNA spliced parts. As the Tat protein is absolutely essential in the process that the DNA of the HIV amendments to the announcement last week of a small molecule inhibitor of the Tat protein was particularly interesting.
However, this is not the only protein of the HIV virus which could be designed to avoid exceeding this reservoir-cell stage. Cells begin to produce RNA display "stress proteins" on its surface, which, although is not clearly outer and therefore attracts a cellular immune response, draws also the attention of the innate immune system - the most evolutionarily ancient less selective, but with a stronger and faster immune response.
These stress proteins bind to a cellular receptor called NKG2D, which is made by natural killer cells, shock forces of the innate immune system. HIV, however, has a protein called Nef, whose one of its duties is to suppress the expression of stress proteins that attract natural killer cells. A small molecule inhibitor of Nef or an anti-Nef vaccine, can block the activity of the nef, increasing the expression of cell stress proteins and generate an innate immune response able to attack 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.
Approaches using the CD4 cells of the individual genes that have their CCR5 receiver removed and are then reinfused into the patient without undergoing drastic step of deleting your entire immune system in the first place and were among the first healing experiments achieved in humans. Matt Sharp, wasone of the first volunteers in this study about healing and this [study] was described as with the most lasting benefits - few side effects and a long push on 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 of University of Pennsylvania managed to cell engineering CD4 cells began to carry on its surface a 'fused peptide ", which is like a necklace, a combination of part of the HIV gp41 fusion protein with receptors CXCR4 or CCR5 receptors. Cells expressing this peptide are fused as they lacked the CCR5 and / or CXCR4 receptors receptors and therefore resistant to HIV infection.
Maintaining the cure of HIV as a priority
This is just a small sample of the many healing strategies and the drug targets explored during 2º day 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 on microbes in treating cell induction of cell vulnerability to infection and studies on the latency. Several other targets on drugs and promising 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 the search for a cure in any discussion of the term AIDS. He was worried, and he said that recent talks on access to treatment, treatment as prevention and pre-exposure prophylaxis (PrEP), and not to mentionobjectives as 90-90-90.
Cure HIV is that it does not want to see come out of the agenda, or go out of the list of priorities of funders. While reducing the incidence of HIV in places as diverse as San Francisco and Botswana are welcome, Sharp adds: only cure and treatment and HIV 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 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 atwww.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