AIDS 2016: HIV Will Only Be Cured with Combined Approaches, Conference Delegates Hear

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Curing people of HIV infection will have to involve combinations of drugs and approaches, just as HIV treatment does, delegates heard at the Towards an HIV Cure workshop held in advance of the recent 21st International AIDS Conference (AIDS 2016) in Durban. The reason is the same, too: HIV can easily develop resistance to single agents, even ones as sophisticated as broadly neutralizing antibodies and gene-editing enzymes.

[Produced in collaboration with Aidsmap.com]

Anthony Fauci, head of the U.S. National Institute of Allergy and Infectious Diseases, told workshop delegates that HIV cure research is roughly at the stage where HIV treatment was in 1990. As with the first HIV drug, AZT (zidovudine), it is becoming clear that single agents or strategies might only have the most limited effect, and dual combinations are starting to show somewhat more promise. Most cutting-edge cure research is still at the stage of lab-dish and animal-model studies, and human trials inevitably lag behind.

Disappointment for One Experimental Combination

Even combinations of approaches do not work if they lack a crucial step in the sequence of events that would need to happen for HIV-infected cells to be purged from the body. The Towards an HIV Cure workshop, and the main AIDS 2016 conference, heard about disappointing results from an experimental regimen consisting of 3 drugs: the immune modulator drug vorinostat, chosen because it can "wake up" the long-lived reservoir cells in which HIV lies hidden; the anti-malaria drug hydroxychloroquine, chosen to contain the immune stimulant effects of vorinostat and prevent runaway HIV infection; and the HIV entry inhibitor maraviroc (Selzentry), chosen because it has the potential to stop HIV spreading to new cells once the reservoir cells are woken up.

This "VHM" combination was given to 10 people with HIV who had been diagnosed within 2 to 4 weeks after infection, treated immediately with antiretroviral therapy (ART), and kept on ART for at least 2 years. Researchers hoped that the "kick" given by this regimen would induce the body’s immune system to spontaneously eliminate the HIV-infected cells that had now become visible to it, or that these cells would convert naturally to a short-lived type that would die.

VHM was given for 10 weeks; after this, all antiretroviral drugs were stopped both in the people who received VHM and in a comparator group of 5 people who got only ART.

It was hoped that the combination might prolong the period people could stay off ART or deplete the size of their viral reservoir. However, viral load rebounded just as fast in the VHM recipients as it did in the participants who received ART alone, and there was no change in the amount of HIV in infected reservoir cells.

Presenter Jintanat Ananworanich told the workshop that the reason VHM did not work was probably because, as other "kick and kill" studies had found, it was not enough to flush the HIV reservoir cells out of hiding. It turned out that the body’s natural immune processes did not then kill these calls and that a "kill" component, or toxin that actively targeted the reawakened reservoir cells, would have to be added.

The study was also a reminder that experimental cure regimens might not be totally harmless; the VHM combination affected the kidneys and blood clotting, and one participant had to stop because of renal insufficiency and low blood platelets.

Two Antibodies Are Better Than One

Fauci also talked about his own laboratory’s work. He is concentrating on the idea of using infusions of broadly neutralizing antibodies (bNAbs). These unusual antibodies have been discovered in the blood of some people with chronic HIV infection, where they have no effect as the virus has already developed resistance to them. But they have a powerful suppressive effect against the virus in some people with shorter-term infection, and can be used as long-lasting injectable drugs, as both treatment and pre-exposure prophylaxis (PrEP). The hope is that a cocktail of bNAbs might eventually have enough suppressive power to enable people to stay off conventional ART for prolonged periods. The ultimate goal is a vaccine or gene therapy that would induce the body to make its own bNAbs.

Fauci showed data from a trial of a bNAb called VRC01 that was given to HIV-positive people 3 weeks before they stopped ART and then again at monthly intervals for 6 months. People resumed ART if their viral load rose above 100 copies/mL or their CD4 cell count fell by more than 30%.

VRC01 did prolong the time people could stay off ART on average, though not by much; compared to people on ART given only a treatment interruption, the time to viral rebound was on average 30 days, rather than 11 days with VRC01. However, while the time to rebound in one patient was as little as 1 week, in 2 other patients the time to rebound was 4 and 5 months, respectively.

What makes the difference is that old bugbear of HIV treatment, resistance. Many people carry pre-existing resistance to specific bNAbs, and in the case of VRC01, this leads to infusions of the antibody only producing 40% more viral control when compared to doing nothing.

There are, however, newly discovered bNAbs out there that are 50 to 100 times more potent than VRC01. There are also accessory drugs that can be used to prolong the half-life of bNAbs in the blood -- adding in a cancer drug called motavizumab, itself an antibody, prolongs the half-life of bNAbs (the time for blood levels of the bNAbs to fall by 50%) from 5 weeks to 6 months.

Ultimately, however, most infusions of single bNAbs will fail because HIV will develop resistance to them. Combination of bNAbs will work better, last longer, and be given at much smaller doses.

Pairs of Gene Scissors

Also at the cure workshop, another study proved that the principle that 2 drugs work better than 1 applies to the high-tech technique of gene editing too. In March, researchers reported on a technique that literally snips the HIV genetic information out of infected cells.

The approach involves infecting cells with lengths of RNA consisting of 2 components: a guide RNA derived from a natural compound called CRISPR, and an endonuclease, a gene-destroying enzyme, called Cas9. The guide RNAs are able to take the Cas9 to the exact point where foreign viral DNA is inserted, so that the cutting and rejoining action of the Cas9 only removes the foreign DNA and causes no collateral damage to nearby genes.

However, as reported only 6 weeks later, the power of the CRISPR/Cas9 "gene missile"’ is short-lived as HIV develops resistance to it very rapidly -- so rapidly that it was feared this might be a dead-end as a cure technique.

But Monique Nijhuis from Utrecht University in the Netherlands showed at the cure workshop that this was happily not the case. Her team has developed 8 different CRISPR/Cas9 gene editors that target different parts of HIV’s genetic sequence. None of these worked well when used singly. However, when cells were infected with 3 specific pairings -- of gene editors called MA3, IN5, and PR2 -- and were then infected with HIV, either a very weak infection followed by complete viral suppression was the result, or in the case of MA3 + PR2, no sign of infection at all, at least for the 55 days the lab study lasted.

Here the gene probes were preventing HIV infection, essentially arming cells with defensive anti-HIV machinery. Nijhuis commented that viral suppression, though so far not quite so profound, was seen when cells were infected with HIV first and CRISPR/Cas9s were then introduced as a treatment.

Gene therapy is at a very early stage of development, and in the case of HIV has not even been tried in animals yet. Nijhuis commented that several challenges remain, including the fact that they did not know why some pairs of gene probes worked better than others and how to accomplish the much more difficult task of infecting the right cells in the body with them rather than simply infecting all the cells in a lab dish. It is also likely to be an expensive approach and hard to adapt for low-income settings. It is, however, encouraging that simply using 2 gene probes instead of 1 has restored potency to what could be an incredibly precise way of removing HIV from the body.

9/8/16

References

A Fauci. Addressing HIV Persistence: Challenges and Opportunities. Keynote address, Towards an HIV Cure workshop, 21st International AIDS Conference (AIDS 2016).

E Kroon, J Ananworanich, K Eubanks, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals initiating ART during acute HIV infection. Towards an HIV Cure workshop, abstract OA3-5LB; 21st International AIDS Conference (AIDS 2016). Durban, July 18-22, 2016. Abstract TUAX0101LB.

M Nijhuis, D de Jong, F Wolters, et al. Combinatorial CRISPR/Cas9 approaches targeting different steps in the HIV life cycle can prevent the selection of resistance. Towards an HIV Cure workshop, abstract OA3-3; 21st International AIDS Conference (AIDS 2016). Durban, July 18-22, 2016. Abstract WEPEA022.