Much remains to be done to find a cure for AIDS
Healing HIV infection will have to involve drug combinations and diverse approaches, only with HIV treatment will not be possible, delegates heard in the Towards to Cure workshop held in advance of the AIDS2016 conference in Durban.
The reason is the same, too: HIV can easily develop resistance to individual agents, as sophisticated as broadly neutralizing antibodies and gene-editing enzymes.
Dr Anthony S. Fauci, Chief of the National Institute of Allergy and Infectious Diseases, told delegates that HIV cure research is about at the same stage of HIV treatment as in 1990; as with the first anti-HIV drug, AZT "zidovudine", it became clear that individual agents or isolated strategies may have only one more limited effect and that combinations of dual therapies were starting to turn out to be a little more promising.
Most of the cutting-edge investigations for the cure are still in phase of laboratory-vitreous lamina and / or in animal model research models and human trials will inevitably have to be postponed for a long time.
Deception for an experimental combination
Even combinations that work lack a crucial step in the sequence of events that would have to happen for HIV-infected cells to be purged from the Human body. The workshop for healing and the main conference, heard of the disappointing results of an experimental scheme consisting of three drugs;
the drug, immune modulator vorinostat chosen because it can "wake up" the reservoir of long-lived cells in which HIV lurks; the antimalarial drug hydroxychloroquine, chosen to contain the effects of vorinostat as an immune stimulant and to prevent defeat for HIV infection; and the maraviroque entry inhibitor, chosen because it has the potential to stop the spread of HIV to new cells, once the cell pool is awakened. This combination of 'VHM' was given to ten people with HIV who had been diagnosed within two to four weeks of infection, immediately treated with antiretroviral therapy (ART) and had been on ART for at least two years.
The 'kick' given by this regimen would be to induce the immune system spontaneously, eliminate the HIV-infected cells that had become visible to it, or would naturally convert to a type of short-lived virus that would die. He hoped that the combination could extend the period in which people
could remain disconnected from ART and / or would impoverish the size of their viral reservoirs. However, in case of viral load they fell as fast in the "target VHM" as in those receiving only ART and there was no change in the amount of HIV infected cells in the reservoir.
Presenter Jintanat Ananworanich told the workshop that the reason VHM did not work was "probably" because, like other "kick-and-kill" studies, they found that this was not enough to "take the reservoir of HIV-infected cells out of clandestinity . It has been found that the body's natural immune processes did not meet these "killer calls" and that a "killer" component or a toxin that actively interferes with the newly awakened target cell reservoir would have to be added.
The study was also a reminder that experimental cures for therapeutic regimens may not be totally harmless; the VHM combination affected kidneys and caused blood clotting problems and one participant had to stop because of renal failure and low platelet count.
Two antibodies are better than one ...
Anthony S. Fauci spoke about his own laboratory work. He is focusing on the idea that with infusions of so-called "widely
neutralizers (bNAbs). These unusual antibodies would have been discovered in the blood of some people chronically infected with HIV, where they have no effect against the virus since it has already developed resistance to them. But they have a potent suppressive effect against the virus in some people with short-term infection and can be used as long-term injectable drugs, both as treatment and / or PrEP. The hope is that a cocktail of bNAbs may eventually have enough suppressive power to allow people to remain disconnected from conventional ART for prolonged periods and the ultimate goal is for a vaccine or gene therapy that would induce the body to make its own bNAbs.
Anthony S. Fauci showed data from the study of a so-called VRC bNAb01 that was given to HIV-positive people three weeks before they stopped ART and then again at half-yearly intervals. People who had their ART stopped or had viral load growth increased above 100 copies / ml or their CD4 count dropped by more than 30%.
The VRC01 was able to extend the time in which people could get out of antiretroviral therapy, on average, though not for long; compared with those on ART, given only an interruption of treatment, the viral rebound time averaged 30 days instead of eleven days. However as time to recover in one patient was only a week in two patients with viral rebound time it was four to five months respectively. (Note from the editor: These data make incongruous therapy and, in my jargon, would be like playing dice with my therapy, to "see what happens")
What makes the difference is the old big bugs of HIV treatment, resistance. Many people have made pre-existing resistance to specific bNAbs and in the case of VRC01 this leads to infusion of antibodies producing only 40% more viral control when compared to doing nothing. (The editor again: "rolling the dice").
There are, however, newly discovered bNAbs that are fifty to one hundred times more potent than VRC01. There are also "drug-enhancers" that can be used to prolong the half-life of these bNAbs in the blood - add in a cancer drug called motavizumab, an antibody itself, prolongs the half-life of the bNAbs (time to blood levels of bNAbs fall 50%) from five weeks to six months. (Editor's Note: Still the data - or roulette, for whomever you prefer)
However, ultimately, more infusions of single bNAbs will fail because HIV will develop resistance to them. Combination of bNAbs would work better, last longer and would be given in much smaller doses.
... and so are two pairs of the "gene scissors"
Also in the healing workshop, another study showed that the principle that two drugs worked better than one that applies the hi-tech technique of editing the
gene as well. Aidsmap reported in March (editor's note: there was simply no time for us to translate this article and it, if it had been translated it would end up "spinning" like so many others who really encouraged us) A technique in which the genetic information of HIV-infected cells was literally edited. It involves infecting cells with RNA lengths consisting of two components: an RNA-derived leader of a natural compound called CRISPR, and an endonuclease, a gene for a cas9 destructive enzyme.
The RNA guide are able to drive cas9 to the exact point where external viral DNA is inserted so that the cut and re-entry of the cas9 action removes only the foreign DNA and does not cause collateral damage in nearby genes.
However, AIDSMAPs as reported later six Semans, the power of the CRISPR / cas9 gene is short and it is vivid as HIV develops resistance to it very quickly - so quickly that one feared it could have been a "dead end" with a "healing technique" .
However Monique Nijhuis of the University of Utrecht, who in the Netherlands showed in a healing workshop that this, fortunately, was not the case. His team has developed eight different CRISPR / cas9 gene editors that target different parts of the HIV genetic sequence. None of these worked well when used alone. However, when the cells were infected with three specific pairs - from the gene publishers called MA3, IN5 and PR2 - and then infected with HIV, a very weak infection followed by complete viral suppression was the result, or in the case of MA3 + PR2 , no sign of infection, at least for the 55 days the lab study lasted.
Here the gene probes were preventing HIV infection essentially arming cells with machinery HIV advocacy; Nijhuis commented that viral suppression, although so far not so deep, was seen where cells were infected with HIV first and then with the CRISPR / cas9s; They were then introduced as a treatment.
Gene therapy is at a very early stage of development and, in the case of HIV, has not yet been attempted even in animals: Nijhuis commented that several challenges remained, including the fact that they do not know why some pairs of gene probes worked best than other pairs, and how to accomplish the much more difficult task of completely infecting all cells in the body, than simply infecting all the cells in a laboratory glassy blade. It is also likely to be an expensive and difficult approach to adapt to low-income settings. However, it is encouraging that simply using two probes instead of one gene has restored potency, which could be a way to unbelievably need to remove HIV from the human body.
Published: July 20 2016
Translated by Claudio Souza Original in Aidsmap entitled HIV will only be cured with combinations too, conference delegates hear reviewed by Mara Macedo on 21 July 2016 AD
Ananworanich J. Effect of vorinostat, hydroxychloroquine and combination therapy on maraviroc viremia Following treatment interruption in Individuals initiating ART During acute HIV infection.Towards a Cure 2016 workshop, Durban, South Africa. Abstract OA3-5LB.
- This was Also presented the abstract at TUAX0101LB at the main aids216 conference - seehttp://programme.aids2016.org/Abstract/Abstract/10535
Fauci A. Addressing HIV Persistence: Challenges and Opportunities. Keynote address, Towards a Cure 2016 workshop, Durban, South Africa.
Nijhuis M. Combinatorial CRISPR / Cas9 approaches targeting different steps in the HIV life cycle can Prevent the selection of resistance. Towards a Cure 2016 workshop, Durban, South Africa. Abstract OA3-3. 2016.
- This was Also presented the abstract at WEPEA022 at the main AIDS conference 2016 - seehttp://programme.aids2016.org/Abstract/Abstract/4228