HIV Cure Work Narrowing in on Antiretroviral-Free Remission

Heather Boerner

November 09, 2017

MILAN — After the failure of many studies to show that latency-reversing agents eradicate HIV, a European consortium is shifting its attention from reservoir to immune response.

"We need an alternative to antiretroviral therapy for life," said Felipe García, MD, from the Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) in Barcelona, Spain. "Shock and kill, as a strategy, does not work alone. I think immune-based therapies are the future."

That "I think" is key. Dr García's approach, which is also the approach of the 14-site European HIVACAR consortium, is currently just a hypothesis. The approach draws on cancer immunotherapy and HIV vaccine research to goose the immune system with therapeutic vaccines, followed by latency-reversing agents.

Shock and kill, as a strategy, does not work alone. I think immune-based therapies are the future.

Dr García presented the protocol, which will be in phase 1/2a trials until 2021, during a European AIDS Treatment Group preconference here at the 16th European AIDS Conference.

Almost every individual step in the HIVACAR protocol has been studied before. The HIVACAR work grows out of the iHIVARNA therapeutic vaccine research Dr García has participated in. And work on broadly neutralizing antibodies is being done at a number of sites, including the National Institutes of Health, where Anthony Fauci, MD, director of the National Institute of Allergies and Infectious Diseases, is conducting a study on the use of an antibody against the cell receptor alpha4beta7 integrin — approved by the US Food and Drug Administration — to induce remission.

Already, that study has shown some promise in animal models, as previously reported by Medscape Medical News.

And, of course, there have been many studies of latency-reversing agents. Those studies have shown how difficult true eradication of the virus is, Dr Fauci told Medscape Medical News.

"People have published papers saying this or that latency-reversing agent eradicated the virus, so they must have cured this individual," Dr Fauci said. "But then they face the real test — discontinuing therapy — and what happens? Inevitably, the virus rebounds."

"The eradication direction of cure research is still existent," he added, "but it's probably not likely." He said he prefers to talk about antiretroviral-free remission instead of cure.

HIVACAR Protocol

That is exactly what Dr García and HIVACAR are considering. The protocol is based on the hypothesis that sustained antiretroviral-free remission can be induced by altering the immune environment, harnessing new parts of the immune system to attack the virus by introducing new epitopes, and targeting dendritic cells to keep HIV from "presenting to the immune system."

First, patients will be randomized to receive one of two intranodal vaccinations. One is meant to be a universal vaccine, Dr García explained, and has already been created by the iHIVARNA collaboration. The second will be specific to each study participant, customized by HIVACAR to block the means of immune escape of that particular virus.

"HIV has vulnerable spots," he said. "We need to target those vulnerable spots."

To understand this approach, think of antiretroviral selection for a patient newly engaged in care. Often, the first step is to search phenotypes for drug-resistant mutations. This is the same thing, only the researchers are looking for mutations in the HIV viruses of individual participants that escape using specific immune pathways, and then seeking to block that escape.

Fifteen days after the vaccine administration, participants will receive injections of broadly neutralizing antibodies, developed using cancer immunotherapy research and research done by the AIDS Vaccine Research Project (HIVACAT) in Spain.

The cancer immunotherapy agents, known as TriMix, have been studied in cancers such as melanoma (Oncoimmunology. 2015;4:e1019197). TriMix combines messenger RNA molecules — caTlR4, CD40L, and CD70 — to try to induce the proliferation of cytotoxic T-cells.

These agents alone have not been successful in controlling cancer, but they have been proven safe. "And they work very well in concert" with other agents, Dr García said.

Importantly, these TriMix agents aim to alter dendritic cells, the little rafts that ferry HIV from point of entry to lymph nodes and herald an immune response.

"If your dendritic cells don't tell your body that you are infected, you don't know that you're infected," he said. "The problem is that dendritic cells have in their membrane some part that's like a glue. And into this glue, the virus puts a viable virus, a live virus. And this virus goes with the dendritic cells to the lymph nodes. It's like a Trojan horse."

But if you can prevent the dendritic cells from carrying that live virus to lymph nodes and T-cells, you might prevent the spread of HIV.

The final step to the protocol comes 2 days after antibody infusion, when investigators will inject a chemotherapy agent to stimulate the virus and attempt to clear the reservoirs.

By then, the hope is that the immune system will be ready for the virus.

"We think a combination of the vaccine and the immune response from the antibodies will be able to control the virus," Dr García said. "But right now, it's a guess. We don't know."

The "Discovery Phase"

That kind of humility is needed in therapeutic vaccine research, said Dr Fauci, who is unfamiliar with the HIVACAR protocol, so he couldn't comment on the specifics. But, he emphasized, it's early days yet.

"We're still in the discovery phase" with antiretroviral-free remission research, he explained. "It's a very active and dynamic field, and if anyone says they have the answer, you should be very suspicious."

If we can show that this can work — and we have not demonstrated that this has worked — it could change the parameters of HIV treatment.

Javier Martinez-Picado, PhD, from the AIDS Research Institute irsiCaixa in Barcelona, said he is excited to see how the combination approach to sustained remission will work, and thinks that targeting dendritic cells is smart. But he said he hasn't given up on clearing the reservoir. In fact, he and his colleagues are working on agents to better clear reservoirs; the research was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2017.

If you can find an efficient enough agent, he said, "it could contribute to viral control in the absence of ART."

But, he added, the emphasis on immunotherapy over reservoir is disquieting.

"My major concern is the limited potency of the latency-reversing agents that will be used in those clinical trials," said Dr Martinez-Picado, who has collaborated with Dr García on the iHIVARNA project, but is not involved in HIVACAR.

For his part, Dr García said he understands the concern. No one knows, really, what will work.

The collaboration "is a proof of concept," he said. "If we can show that this can work — and we have not demonstrated that this has worked — it could change the parameters of HIV treatment."

HIVACAR is funded by the European Commission of the European Union. The European AIDS Treatment Group receives funding from Gilead Sciences, Merck, Sharp & Dome, Janssen Pharmaceuticals, and ViiV Healthcare. Dr García, Dr Fauci, and Dr Martinez-Picado have disclosed no relevant financial relationships.

16th European AIDS Conference. Presented October 24, 2017.

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