US Pharm. 2024;49(10):35-38.

New Drug Shows Promise in Clearing HIV From Brain

An experimental drug originally developed to treat cancer may help clear HIV from infected cells in the brain, according to a new Tulane University study. For the first time, researchers at Tulane National Primate Research Center found that a cancer drug significantly reduced levels of simian immunodeficiency viruses, the nonhuman primate equivalent of HIV, in the brain by targeting and depleting certain immune cells that harbor the virus.

Published in the journal Brain, this discovery marks a step toward eliminating HIV from hard-to-reach reservoirs where the virus evades otherwise effective treatment.

“This research is an important step in tackling brain-related issues caused by HIV, which still affect people even when they are on effective HIV medication,” said lead study author Woong-Ki Kim, PhD, associate director for research at Tulane National Primate Research Center.

“By specifically targeting the infected cells in the brain, we may be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment,” Dr. Kim added.

Antiretroviral therapy (ART) is an essential component of successful HIV treatment, maintaining the virus at undetectable levels in the blood and transforming HIV from a terminal illness into a manageable condition. However, ART does not completely eradicate HIV, necessitating lifelong treatment. The virus persists in viral reservoirs in the brain, liver, and lymph nodes, where it remains out of reach of ART.

The brain has been a particularly challenging area for treatment due to the blood-brain barrier—a protective membrane that shields it from harmful substances but also blocks treatments, allowing the virus to persist. In addition, cells in the brain known as macrophages are extremely long-lived, making them difficult to eradicate once they become infected.

Infection of macrophages is thought to contribute to neurocognitive dysfunction, experienced by nearly half of those living with HIV. Eradicating the virus from the brain is critical for comprehensive HIV treatment and could significantly improve the quality of life for those with HIV-related neurocognitive problems.

Could Vaccine Concept Produce Multiple HIV-Neutralizing Antibodies?

Using a combination of cutting-edge immunologic technologies, researchers successfully stimulated animals’ immune systems to induce rare precursor B cells of a class of HIV broadly neutralizing antibodies (bNAbs). The findings, published in Nature Immunology, are an encouraging incremental step in developing a preventive HIV vaccine.

HIV is genetically diverse, making the virus difficult to target with a vaccine, but bNAbs may overcome that hurdle because they bind to parts of the virus that remain constant even when it mutates. Germline targeting is an immune system–stimulating approach that guides naïve (precursor) B cells to develop into mature B cells that can produce bNAbs.

A class of bNAbs called 10E8 is a priority for HIV vaccine development because it neutralizes a particularly broad range of HIV variants. The 10E8 bNAb binds to a conserved region of the glycoprotein gp41 on HIV’s surface involved in its entry into human immune cells. Designing an immunogen—a molecule used in a vaccine that elicits a specific immune system response—to stimulate production of 10E8 bNAbs has been challenging because the key region of gp41 is hidden in a recessed crevice on HIV’s surface. Prior vaccine immunogens have not generated bNAbs with the physical structure to reach and bind to gp41.

To address this challenge, the researchers engineered immunogens on nanoparticles that mimic the appearance of a specific part of gp41. They vaccinated rhesus macaque monkeys and mice with these immunogens and elicited specific responses from the 10E8 B cell precursors, inducing antibodies that showed signs of maturing into bNAbs that could reach the hidden gp41 region. They observed similar responses when they used mRNA-encoded nanoparticles in mice. The researchers also found that the same immunogens produced B cells that could mature to produce an additional type of gp41-directed bNAb called LN01. Finally, their laboratory analysis of human blood samples found that 10E8-class bNAb precursors occurred naturally in people without HIV and that their immunogens bound to and isolated naïve human B cells with 10E8-like features.

Common HIV Treatments May Help Alzheimer’s Disease Patients

Alzheimer’s disease (AD) currently afflicts nearly 7 million people in the United States. With this number expected to grow to nearly 13 million by 2050, the lack of meaningful therapies represents a major unmet medical need. Scientists at Sanford Burnham Prebys have identified real-world links between common HIV drugs and a reduced incidence of AD. The study, led by Jerold Chun, MD, PhD, was published in Pharmaceuticals.

Dr. Chun’s new research builds on his laboratory’s landmark publication in Nature in 2018 that described how somatic gene recombination in neurons can produce thousands of new gene variants within AD brains. Importantly, it also revealed for the first time how the Alzheimer’s-linked gene, APP, is recombined by using the same type of enzyme found in HIV.

The enzyme, called reverse transcriptase (RT), copies RNA molecules and changes them into complementary DNA duplicates that can then be inserted back into DNA, producing permanent sequence changes within the cell’s DNA blueprint.

HIV and many other viruses rely on RT to hijack a host’s cells to establish a chronic infection, so drugs that block the RT enzyme’s activity have become a common part of treatment cocktails for keeping HIV at bay.

The brain appears to have its own RTs that are different from those in viruses, and the research team wondered if inhibiting brain RTs with HIV drugs helps AD patients.

To assess the link between real-world RT inhibitor exposure and AD in humans, the team analyzed anonymized medical records with prescription claims from more than 225,000 control and HIV-positive patients. The scientists found that RT inhibitor exposure was associated with a statistically significant reduced incidence and prevalence of AD.

“Thus, we looked at HIV-positive individuals taking RT inhibitors and other combined antiretroviral therapies as they aged and asked the question: How many of them got Alzheimer’s disease?,” explained Dr. Chun. “And the answer is that there were many fewer than might have been expected compared to the general population.”

Of the more than 225,000 individuals with claims data in the study, just shy of 80,000 were HIV-positive individuals aged older than 60 years. More than 46,000 had taken RT inhibitors during a nearly 3-year observation period from 2016 to 2019. The data were obtained through a collaboration with health information technology and clinical research firm IQVIA, led by Tiffany Chow, MD.

In living persons with HIV, there were 2.46 AD diagnoses per 1,000 persons among HIV-positive individuals taking these inhibitors, versus 6.15 for the general population. This control group was represented by more than 150,000 HIV-negative patients aged older than 60 years with medical insurance claims related to treatment for the common cold.

“You cannot feasibly run a prospective clinical trial with this number of patients,” Dr. Chun added. “This approach is a way to look at how a drug can act on a large patient population.”

Dr. Chun underscored that the drugs patients took in this retrospective study were designed to counter RT activity in HIV and likely only had a limited effect on many different possible forms of the enzyme active in the brain.

“What we’re looking at now is very crude,” said Dr. Chun. “The clear next step for our lab is to identify which versions of RTs are at work in the AD brain so that more targeted treatments can be discovered, while prospective clinical trials of currently available RT inhibitors on persons with early AD should be pursued.”

GPS-Like System May Elicit Critical HIV Antibodies

A team led by the Duke University Human Vaccine Institute (DHVI) has developed a vaccine approach that works like a GPS, guiding the immune system through the specific steps to make broadly neutralizing antibodies against HIV.

Published in the journal Cell Host & Microbe, the study described an approach that provides step-by-step directions for the immune system to generate the elusive, yet necessary, antibodies for a successful HIV vaccine.

“HIV is the fastest-evolving virus known. So it’s been a long-standing goal in HIV research to create a vaccine that can generate broadly neutralizing antibodies that can recognize diverse HIV strains,” said lead author Kevin Wiehe, PhD, associate professor in the Department of Medicine at Duke University School of Medicine and director of research at DHVI.

Dr. Wiehe and colleagues started with an engineered version of a broadly neutralizing antibody in its original state, before any mutations occurred. Knowing that the antibody will need to mutate to keep up with the ever-changing HIV virus, the researchers then added sequential mutations one-by-one to determine which mutations were essential for the antibody to broadly neutralize HIV.

Doing this allowed them to figure out what the exact points were along the route to arrive at broadly neutralizing antibodies. They then developed a vaccine that gave the immune system the turn-by-turn directions to follow that mutational route.

Using mice specially bred to encode for the original version of the antibody, the researchers demonstrated that the guidance system approach triggered the immune system to start churning out the sought-after antibodies.

“This paper shows that our mutation-guided vaccine strategy can work,” said Dr. Wiehe, adding that the technique could also be used in vaccines for other diseases. “This strategy potentially gives us a way to design vaccines to direct the immune system to make any antibody we want, which could be a broadly neutralizing antibody for all coronavirus variants or an anti-cancer antibody.” Dr. Wiehe said the next challenge will be to reproduce the study in primates and then humans.

New Method Developed to Isolate HIV Particles

Researchers at Leipzig University and Ulm University in Germany have developed a new method to isolate HIV from samples more easily, potentially making it easier to detect infection with the virus. The focus is on peptide nanofibrils (PNFs) on magnetic microparticles, a promising tool and hybrid material for targeted binding and separation of viral particles. They published their new findings in the journal Advanced Functional Materials.

“The presented method makes it possible to efficiently capture, isolate, and concentrate virus particles, which may improve the sensitivity of existing diagnostic tools and analytical tests,” said Bernd Abel of the Institute of Technical Chemistry at Leipzig University.

The nanofibrils used, small, needle-like structures, are based on the EF-C peptide, which was first described in 2013 by Jan Münch from Ulm University and Ulm University Medical Center. EF-C is a peptide consisting of 12 amino acids that forms nanoscale fibrils almost instantaneously when dissolved in polar solvents.

These can also be applied to magnetic particles. “Using the EF-C peptide as an example, our work shows how peptide fibrils on magnetic particles can have a completely new functionality—the more or less selective binding of viruses. Originally, fibrils of this kind were more likely to be associated with neurodegenerative diseases,” added Torsten John, co–first author of the study and former doctoral researcher under Dr. Abel at Leipzig University and currently a junior researcher at the Max Planck Institute for Polymer Research in Mainz, Germany.

“Increasing the local concentration and isolating viruses from samples are critical to increasing the sensitivity of diagnosing viral infections,” said Dr. Münch. The researchers from Ulm and Leipzig have presented a method for the concentration and isolation of HIV particles. In their study, they show how PNFs can be used effectively to separate HIV particles from solutions without relying on centrifugation.

By improving the efficiency with which virus particles can be concentrated and isolated, this technology and the new hybrid material could help to improve the diagnosis of infections and the monitoring of resistance, the scientists said.

Study Seeks Functional Cure for HIV

Researchers from George Mason University’s Center for Infectious Disease Research (CIDR) and Tulane National Primate Research Center conducted a breakthrough proof-of-concept study in Nature’s Gene Therapy that found an HIV-like virus particle that could cease the need for lifelong medications. Scientists have made great strides in the treatment of HIV over the past few decades, yet people with the virus must still take antiretroviral therapy (ART) for life as the disease is difficult to eradicate.

Researchers at CIDR, led by Yuntao Wu, professor in George Mason’s School of Systems Biology and the principal investigator of the National Institutes of Health (NIH)–funded study, developed a special HIV-like virus particle, called HIV Rev-dependent lentiviral vector, that uses an HIV protein, Rev, as a trigger to selectively target and activate therapeutic genes in HIV-infected cells. The George Mason team has been developing the HIV Rev-dependent vector technology since 2002.

According to Dr. Wu, patients need to take medications for the rest of their lives because of the persistence of HIV reservoirs, which are infected immune cells harboring the virus. Currently, ART used by patients can effectively block the virus, but it cannot eliminate the viral reservoirs. Experimental approaches such as “shock and kill” and “block and lock” of the reservoirs have been in development to either eliminate or silence viral reservoirs. Dr. Wu said the HIV Rev–dependent lentiviral vector technology uses a different approach that relies on the HIV Rev protein to selectively target reservoirs for killing or for inactivation.

“Our approach shows signs of not only reducing viral reservoirs but also boosting the immune system to produce antiviral neutralizing antibodies,” he said. “Think about turning a bad guy into a good one.”

The reservoir cells can be targeted by the Rev-dependent vector and be turned into releasing defective viruses that can act as a vaccine to stimulate neutralizing antibodies. Dr. Wu’s team named this new approach “rehab and redeem” of the HIV reservoirs.

Scientists at Tulane National Primate Research Center collaborated with Dr. Wu’s team to test this technology on monkeys infected with SIVmac239 (a virus similar to HIV), finding that the virus levels in the blood and brain in one monkey have been reduced to undetectable most of the time for over 2 years after ceasing to administer ART.

According to Brian Hetrick from George Mason, this approach shows promise in controlling viremia and opens new avenues for developing effective treatments for HIV without relying on daily antiretrovirals.

“Our proof-of-concept animal studies demonstrate a step forward in the fight against this virus, bringing us closer to innovative and potentially transformative therapies for HIV patients,” said Dr. Hetrick.

This proof-of-concept study signals technologies that could come for the 1.2 million people in the United States and 39 million worldwide (as of 2022) with HIV who depend on medications to keep the virus under control. Additional funded studies are needed to expand and optimize the animal studies, followed by human clinical trials.

Dr. Wu thanked the NYCDC AIDS Ride organized by Marty Rosen that raised funding to keep his team going in early years, leading to the more recent NIH-supported animal trial. “It took us 20 years to walk the first step; we will certainly keep going,” Dr. Wu said.

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