New trial highlights incremental progress towards a cure for HIV-1
CHAPEL HILL, N.C. – Antiretroviral therapies (ART) stop HIV replication in its tracks, allowing people with HIV to live relatively normal lives. However, despite these treatments, some HIV still lingers inside cells in a dormant state known as "latency." If ART is discontinued, HIV will awaken from its dormant state, begin to replicate, and cause acquired immunodeficiency syndrome (AIDS). To create a cure, researchers have been attempting to drive HIV out of latency and target it for destruction.
A new clinical trial led by Cynthia Gay, MD, MPH, associate professor of infectious diseases, David Margolis, MD, the Sarah Kenan Distinguished Professor of Medicine, Microbiology & Immunology, and Epidemiology, and other clinicians and researchers at the UNC School of Medicine suggests that a combination of the drug vorinostat and immunotherapy can coax HIV-infected cells out of latency and attack them.
The immunotherapy was provided by a team led by Catherine Bollard, MD, at the George Washington University, who took white blood cells from the study participants and expanded them in the laboratory, augmenting the cells’ ability to attack HIV-infected cells, before re-infusion at UNC.
Their results, published in the Journal of Infectious Diseases, showed a small dent on the latent reservoir, demonstrating that there is more work to be done in the field.
“We did show that this approach can reduce the reservoir, but the reductions were not nearly large enough, and statistically speaking were what we call a “trend” but not highly statistically significant,” said David Margolis, MD, director of the HIV Cure Center and senior author on the paper. “We need to create better approaches to flush out the virus and attack it when it comes out. We need to keep chipping away at the reservoir until there's nothing there.”
DNA inside cell nuclei is kept in a tightly packed space by chromosomes, which act as highly organized storage facilities. When you unfurl a chromosome, you'll find loop-de-loop-like fibers called chromatin. If you keep unfurling, you'll see long strands of DNA wrapped around scaffold proteins known as histones, like beads on a string. Finally, when the unfurling is complete, you will see the iconic DNA double helix.
Vorinostat works by inhibiting a lock-like enzyme called histone deacetylase. By stopping this mechanism, tiny doors within the chromatin fibers unlock and open up, effectively “waking up” latent HIV from its slumber and making it vulnerable to an immune system attack. As a result, a tiny blip of HIV expression shows up on very sensitive molecular assays.
But the effects of vorinostat are short lived, only lasting a day per dose. For this reason, Margolis and other researchers are trying to find safe and effective ways to administer the drug and keep the chromatin channels open for longer periods of time.
For the study, six participants were given multiple doses of vorinostat. Researchers then extracted immune cells from the participants and expanded the cells that knew how to attack HIV-infected cells.
This immunotherapy method, which has been successful against other viruses such as Epstein-Barr virus and cytomegalovirus, involves giving participants back their expanded immune cells in the hopes that these cells will further multiply in number and launch an all-out attack on the newly exposed HIV-infected cells.
However, in the first part of this study, only one of the six participants saw a drop in their HIV reservoir levels. To test whether the result was simply random or something more, researchers gave three participants their usual dose of vorinostat, but introduced five times the amount of engineered immune cells. All three of the participants had a slight decline in their reservoirs.
But, statistically speaking, the results were not large enough to be definitive.
“This is not the result we wanted, but it is research that needed to be done,” said Margolis. “We are working on improving both latency reversal and clearance of infected cells, and we hope to do more studies as soon as we can, using newer and better approaches.”
Many of the participants in the study have been working with Margolis’s research team for years, sacrificing their own time and blood for research efforts. Their long-term partnership and commitment have been essential for data collection. The data, which follows the size of the viral reservoir in these people over years prior to this study, makes the small changes found more compelling.
“People living with HIV come in a couple of times a year, and we measure residual traces of virus in their blood cells, which doesn’t have any immediate benefit to them,” said Margolis. “It’s a very altruistic action and we couldn't make any progress without their help.”
About UNC School of Medicine
The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 7th overall for primary care by US News & World Report, and 7th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.
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JOURNAL
The Journal of Infectious Diseases
SUBJECT OF RESEARCH
Not applicable
ARTICLE TITLE
The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy
ARTICLE PUBLICATION DATE
13-Feb-2024
Stopping HIV in its tracks
Just over a year ago, the European Union and the US Food and Drug Administration approved a new anti-retroviral drug to treat human immunodeficiency virus (HIV) infections. Lenacapavir is the first drug available to patients that is designed to home in on the HIV’s protective armour – the HIV capsid.
An international team of researchers led by UNSW Sydney medical researchers now have the details on how this novel drug pushes the HIV capsid to breaking point, stopping the virus in its tracks. The molecular mechanisms that they uncovered are published in the journal eLife, and could help to refine and design more effective anti-viral therapies.
HIV encases its genetic material in a protein coat to safeguard the virus as it converts its genomic RNA into DNA enroute to the nucleus after entering the target cell. Developed by biopharmaceutical company Giliad Sciences, lenacapavir was designed to thwart this very protection afforded by the capsid. And this potent and long-acting drug is the first, and so far the only, approved anti-HIV therapy to do so.
“The fact that the capsid plays a central role in multiple stages of the viral life cycle, and therefore represents a really good drug target, is a concept that's only emerged in recent years,” said Professor Till Böcking, who led the team together with Dr David Jacques.
Building them tough to break them down
By combining cell infection studies with single-molecule imaging, the researchers showed how lenacapavir disrupted the HIV life cycle. Some theorised that the drug hardens the capsid to lock the virus in, thereby preventing it from establishing infection. Instead, the team saw that the capsid, fortified by the drug, actually became very brittle.
“What we found was that this hyper-stabilization actually led to a premature breakage of the capsid, before the virus can finish converting its RNA into DNA,” Professor Böcking said.
In the target cell, the capsid would rupture before the virus reaches the nucleus, leaving its genetic material exposed to the hostile environment in the host cell cytoplasm. To study the effect of lenacapavir on individual capsids over time, the team worked with non-infectious HIV-like particles produced by cells.
“With our microscope setup, we can look at the integrity of the capsids. By monitoring the release of fluorescent tags loaded into the capsid, we can work out exactly when it cracks,” said Dr Walsh, one of the study’s lead authors.
With Dr Leo James and other colleagues in the Laboratory of Molecular Biology in the UK, the team also examined the building of new capsids, recreating a process that would take place after newly made copies of the viral genome are bundled up for release from infected cells. They found that lenacapavir sabotaged capsid integrity at this phase of the HIV life cycle as well by accelerating the capsid construction to force construction errors. The deformed capsids that were produced were unable to close properly and would fail to shield the viral genome from attack.
This study not only settles the debate over whether capsid-targeting drugs strengthen or weaken the capsid, the uncovered mechanism could also be exploited for targeting other viruses that build capsids to shelter from host defences.
“Lenacapavir is orders of magnitude better than any other compound that targets the capsid. Our results give a really good blueprint for how this drug is able to be so incredibly effective,” said Dr Walsh.
JOURNAL
eLife
METHOD OF RESEARCH
Experimental study
ARTICLE TITLE
Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure
ARTICLE PUBLICATION DATE
13-Feb-2024
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