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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 Sez-Cirin, 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 Sez-Cirin 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 Sez-Cirin.
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

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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

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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 Sez-Cirin, 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.

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Cite this article: HIV Cure Advancing From Isolated Cases to Clinical Trials. Medscape. Jul 24, 2015.

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