HIV Cure Advancing From Isolated Cases to Clinical Trials

Pam Harrison

July 24, 2015

VANCOUVER, British Columbia — A French teenager is now the longest-lived pediatric patient ever infected with HIV who is no longer on antiretroviral therapy. She was treated with zidovudine prophylaxis at birth, and then received antiretrovirals for 6 years.

Twelve years after discontinuing treatment altogether, the viral load of the teen, now 18 and a half years old, is undetectable, even when measured with a highly sensitive assay that can detect less than 4 copies of HIV RNA/mL. And her CD4 count has remained stable.

"We know that she is still infected — we can detect HIV DNA in the cells of this girl — but viral replication in the plasma is undetectable," Asier Sáez-Cirión, PhD, from Institut Pasteur in Paris, told reporters attending a news conference here at the 8th International AIDS Society Conference, where HIV cure researchers discussed advances in the field.

"We actually can reactivate viral replication when we isolate cells and reactivate them in the laboratory," he explained. "With the highly documented case of this young woman, we provide the proof of concept that long-term remission is possible in children, as in adults, although these cases are still very rare."

This particular case is clinically, immunologically, and virologically similar to that of adults in the l'Agence nationale de recherche sur le SIDA VISCONTI study.

The VISCONTI Study

In 2014, researchers reported that 14 adults — called post-treatment controllers — continued to achieve virologic and immunologic control of their infection, without receiving antiretroviral therapy, for a median of 10 years. The VISCONTI cohort had received treatment for a median of 3 years before they discontinued therapy.

Starting antiretroviral therapy during primary infection can reduce HIV viral reservoirs and preserve immune responses, protecting patients from chronic immune activation, Dr Sáez-Cirión and colleagues write in a report on the 14 patients in the VISCONTI cohort (PLoS Pathog. 2013;9:e1003211).

"We have observed that some HIV-infected patients who interrupted prolonged antiretroviral therapy initiated close to primary infection are able to control viremia afterward," said Dr Sáez-Cirión.

In detailing the progress — or lack thereof — of these 14 patients, Dr Saez-Cirion's team notes that the capacity of these post-treatment controllers is likely related to early therapeutic intervention.

"We found that post-treatment controllers were able, after therapy interruption, to keep, and in some cases further reduce, a weak viral reservoir," they explain.

A long-lived viral reservoir is likely a major obstacle to achieving a cure for HIV.

Another high-profile example of a pediatric patient who achieved at least a limited remission after the administration of antiretrovirals is the so-called Mississippi baby.

The Mississippi Baby

Like the French teen, the Mississippi baby became infected by her mother around the time of her birth. Physicians initiated highly active antiretroviral therapy within 30 hours of birth. The child appeared to have achieved a "sterilizing" cure after the rapid initiation of antiretrovirals and treatment was withdrawn.

However, 27 months after treatment had been discontinued, the child experienced a viral rebound and physicians reinstated antiretroviral therapy.

HIV cure researchers — capitalizing on the concept that a few HIV-infected patients have some unique feature of their immune response that can successfully suppress the virus — are working on highly innovative strategies to boost the immune system exogenously.

The first of these immune-enhancing strategies uses broadly neutralizing antibodies.

Innovative Shock and Kill Strategies

"Over the past 5 or 10 years, the field has come to understand that some individuals make remarkably potent antibodies against the virus. Researchers have been able to isolate these antibodies, and we now have them in hand as potential clinical products for the prevention or treatment of HIV infection," John Mascola, MD, from the Vaccine Research Center at the National Institute of Allergy and Infectious Disease in Bethesda, Maryland, said during the news conference.

These neutralizing antibodies could be a whole new way of getting at the virus, he explained. As the antibodies circulate throughout the system, they should be able to recognize, attack, and then kill cells that are infected with HIV, which antiretrovirals cannot do. "Antibodies are also likely to have a very low side-effect profile," Dr Mascola told Medscape Medical News.

"We can see them being used as prevention because they could actually block infection, and they can last a long time, so they could be persistently present to kill virus that tries to reactivate," he added.

Preliminary work has to establish whether these exogenous antibodies will keep the virus suppressed. "If the antibodies look to be very active, they will be used in 'shock and kill' approaches," said Dr Mascola.

In shock and kill, immune stimulants shock the latent virus from hidden reservoirs and then attempt to kill reactivated HIV. The stimulants could be broadly neutralizing antibodies, such as those engineered by Dr Mascola and colleagues, or a vaccine, which is being tested in an early prospective trial conducted by the CHERUB collaboration.

Another approach that has shown early promise is the use of hematopoietic stem cells that have been genetically engineered to resist infection through the targeted disruption of the CCTR5 gene.

The CCR5 receptor allows the virus to infect cells, including T-cells.

Genetically Engineered Stem Cells

"By engineering stem cells and transplanting them back into our primate model, stem cells give rise to different sorts of blood cells, and we can show that we can protect T-cells that shouldn't allow the virus to infect them," said Christopher Peterson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.

If enough of these protected cells are circulating in the body, the virus won't be able to spread, which would lead to a functional cure.

Even if only a proportion of the cells are protected by engineered stem cells, they would still be able to respond more robustly to the virus, and that would have a beneficial effect on the whole immune system, he explained.

"Cells that are primarily being attacked by the virus — the CD-positive T-cells — are the same cells that are responsible for coordinating the immune response against the virus," Dr Peterson said. "The best soldiers for this particular foe are the first ones that are falling."

"The fact that we can protect even a subset of those cells has been shown to be beneficial, so we are using this gene-editing strategy, along with other strategies, to block the ability of the virus to get into the cell," he explained. "Even with 10% of cells being protected, we see cells that are able to destroy virus-infected cells."

The so-called Berlin patient is the only person who has ever been cured of HIV; he received a bone marrow transplant from a donor with a natural mutation in the CCR5 receptor.

Managing Expectations

"It's very important to report work that is exciting, like this French teenager," said Lynda Dee, from AIDS Action Baltimore. However, "it's also very important to keep expectations reasonable for the community so that people don't think there is a cure for AIDS."

"People have tendency to look at the 'top line' of stories and think, 'okay, well AIDS is over now'," she said.

"We need to be very careful about how these things are reported and understand that the work that is being done, while not a home run, leads to first-base and second-base hits, where people who deal with HIV will have a better quality of life and reduced morbidity and mortality."

Dr Sáez-Cirión, Dr Mascola, and Ms Dee have disclosed no relevant financial relationships. Dr Peterson does research in collaboration with Sangamo Biosciences.

8th International AIDS Society (IAS) Conference: Abstract MOAA0105LB, presented July 20, 2015; abstract TUAA0202, presented July 21, 2015.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....