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A multi-institutional team led by Weill Cornell Medicine investigators has been awarded a five-year, $20.8 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, for advanced preclinical development of a promising experimental HIV vaccine.

A successful vaccine to prevent new HIV infections would be a major public health breakthrough. About 1.3 million people acquired HIV in 2024, according to the World Health Organization, and at the end of that year an estimated 41 million people were living with the virus. Medication can keep individuals healthy but must be taken for a lifetime.

Prior studies of the new experimental vaccine suggest that it is safe and may be effective when administered early in life. In the work funded by the grant, the researchers will optimize the vaccine in preparation for clinical trials in infants, in parts of the world with high HIV burden.

“The ability to induce effective immunity, in childhood, against a broad set of HIV variants could revolutionize HIV prevention efforts and ultimately bring this decades-long pandemic to an end,” said lead investigator Dr. Sallie Permar, chair of the Department of Pediatrics and the Nancy C. Paduano Professor in Pediatrics at Weill Cornell Medicine and pediatrician-in-chief at NewYork-Presbyterian Komansky Children’s Hospital of Children’s Hospital of New York. 

The main co-investigator of the project is Dr. Kristina De Paris, a professor in the Department of Microbiology and Immunology at UNC School of Medicine.

Effectively immunizing against HIV has been a seemingly insurmountable challenge ever since the virus was identified as the cause of AIDS in 1983. The HIV proteins that are most accessible to the immune system mutate rapidly, essentially leading the immune response on a fruitless and unending chase. HIV does have relatively non-varying structures that it uses to gain entry into host cells, but these are hard for the immune system to “see,” in part because the virus shields them with antibody-resistant sugar molecules called glycans. Studies of people with HIV have found rare antibodies that can nevertheless fasten onto HIV’s vulnerable sites, thus blocking the virus’s infectivity across a broad set of strains. But a vaccine that can elicit these “broadly neutralizing” antibodies (bnAbs) in sufficient quantities has been elusive.

Currently one of the most promising HIV vaccine strategies is to use engineered versions of Env, HIV’s outer-envelope protein complex. The Env complex, which is critical for HIV’s infectivity, assembles on the viral surface in a delicate, three-part “trimer” structure. In research spanning the last quarter-century and spearheaded largely by Dr. John Moore, professor of microbiology and immunology at Weill Cornell Medicine, Dr. Rogier Sanders, now a professor at Amsterdam UMC and an adjunct associate professor of research in microbiology and immunology at Weill Cornell Medicine and Dr. Ian Wilson and Dr. Andrew Ward at Scripps Research, scientists have managed to engineer versions of the Env trimer that can exist on their own without falling apart, while retaining the ability to elicit bnAbs. The experimental vaccine that Dr. Permar and her colleagues will be testing is based on the most recently optimized trimer structure, known as the BG505 GT1.1 SOSIP trimer. It is designed to be administered in a series of inoculations that, over time, direct the antibody response toward the production of bnAbs.

Traditionally vaccines are tested in children after they have been proven effective in adults. However, initial clinical trials in adults and preclinical work in a rhesus macaque model of HIV suggest that the Env trimer vaccine can elicit useful quantities of bnAbs only in young immune systems.

This is good news for the potential success of the vaccine, as the number of boosts and length of time needed to achieve an effective anti-HIV response make it optimal to place an HIV vaccine within the childhood vaccine schedule.” 

Dr. Sallie Permar, chair of the Department of Pediatrics and the Nancy C. Paduano Professor in Pediatrics, Weill Cornell Medicine

“It may be that our only opportunity for an effective HIV vaccine is to test it as a childhood vaccine,” she added.

The overarching goal of the new research program is therefore to advance the work that has been done on the Env trimer vaccine, to help pave the way for initial clinical trials of it as a pediatric vaccine.

“We’ll be optimizing the dose of the Env trimer protein complex and the general immune-boosting ‘adjuvant’ compound that we use in vaccines, as well as the number and schedule of inoculations,” said Dr. Ashley Nelson, an assistant professor in the department of pediatrics at Weill Cornell Medicine.

A sub-project headed by Dr. Genevieve Fouda, professor of pediatrics at Weill Cornell Medicine, will examine how other childhood immunizations might alter the effectiveness of the experimental HIV vaccine.

“In places like sub-Saharan Africa where the rate of vertical HIV transmission is high, newborns could be protected by passive immunization with anti-HIV bnAbs during breastfeeding and would concurrently be given standard childhood vaccines,” Dr. Fouda said. “We will study whether these have any interaction with the experimental vaccine.” 

Dr. De Paris will lead the immune analytics sub-project, in which Dr. Moore and his team will produce the BG505 GT1.1 SOSIP trimer and evaluate the antibody responses it elicits.” The vaccine tests, in rhesus macaques, will be conducted by Dr. Koen Van Rompay, core scientist in the California National Primate Research Center at UC Davis.

Twenty-seven species of bacteria and fungi among the hundreds that live in people’s mouths have been collectively tied to a 3.5 times greater risk of developing pancreatic cancer, a study led by NYU Langone Health and its Perlmutter Cancer Center shows.

Experts have long observed that those with poor oral health are more vulnerable to pancreatic cancer than those with healthier mouths. More recently, scientists have uncovered a mechanism that could help explain this connection, finding that bacteria can travel through swallowed saliva into the pancreas, an organ that helps with digestion. However, precisely which species may contribute to the condition had until now remained unclear.

Publishing online Sept. 18 in JAMA Oncology, the new analysis assessed the genetic makeup of microbes collected from the saliva of 122,000 healthy men and women.

Our findings provide new insight into the relationship between the oral microbiome and pancreatic cancer.”

Yixuan Meng, PhD, study lead author, postdoctoral fellow, Department of Population Health, NYU Grossman School of Medicine

The oral microbiome, the diverse community of bacteria and fungi that inhabit the mouth, is increasingly being studied for its potential role in human health.

Last year, the same team of scientists uncovered a link between certain oral bacteria and a heightened risk of developing head and neck squamous cell carcinoma, a group of cancers that arise in the mouth and throat. The researchers had also conducted a small study in 2016 that tied microbes living in the mouth to pancreatic cancer, but could not identify precise bacterial species.

Their latest report is the largest and most detailed analysis of its kind to date, says Meng. It is also the first to show that oral fungi – namely a type of yeast called Candida that naturally lives on the skin and throughout the body – may play a role in pancreatic cancer. The researchers also identified these oral Candida species in patients’ pancreatic tumors.

For the study, the team assessed data from two ongoing investigations tracking Americans from across the country to better understand how diet, lifestyle, medical history, and many other factors are involved in cancer. The data were gathered for the American Cancer Society Cancer Prevention Study II and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Shortly after enrolling, participants rinsed with mouthwash, providing saliva samples that preserved the numbers and species of microbes for testing. Researchers then followed up for roughly nine years on average to record any presence of tumors.

In the current study, the investigators analyzed bacterial and fungal DNA from the spit samples. Then, they identified 445 patients who were diagnosed with pancreatic cancer and compared the DNA of their microbes with that of another 445 randomly selected study subjects who had remained cancer free. The team made sure to account for factors known to play a role in developing the condition, such as age, race, and how often subjects smoked cigarettes.

The findings identified 24 species of bacteria and fungi that individually either raised or lowered pancreatic cancer risk. Another three kinds of bacteria tied to the cancer were already known to contribute to periodontal disease, a serious gum infection that can eat away at the jawbone and the soft tissues surrounding teeth.

Altogether, the entire group of microbes boosted participants’ chances of developing the cancer by more than threefold.

In addition, by assessing the makeup of each participant’s oral microbiome, the scientists for the first time developed a tool that could estimate their cancer risk.

“By profiling bacterial and fungal populations in the mouth, oncologists may be able to flag those most in need of pancreatic cancer screening,” said study co-senior author Jiyoung Ahn, a professor in the Departments of Population Health and Medicine at NYU Grossman School of Medicine.

Ahn, who is also the associate director for population sciences at Perlmutter Cancer Center, notes that there are currently few effective screening methods for the disease, which is among the deadliest forms of cancer.

“It is clearer than ever that brushing and flossing your teeth may not only help prevent periodontal disease but may also protect against cancer,” said study co-senior author Richard Hayes, DDS, MPH, PhD, a professor in the Department of Population Health at NYU Grossman School of Medicine.

Hayes, who is also a member of Perlmutter Cancer Center, emphasizes that the study was designed to identify correlations between disease risk and certain microbes in the mouth, but not to establish a direct cause-and-effect link. That will require further investigation.

The research team next plans to explore whether oral viruses could contribute to cancer and how the mouth’s microbiome may affect patients’ chances of survival, adds Hayes.

Funding for the study was provided by National Institutes of Health grants P30CA016087, P20CA252728, R01LM014085, R01CA159036, and U01CA250186.

Along with Meng, Hayes, and Ahn, other NYU Langone researchers involved in the study are Feng Wu, PhD; Soyoung Kwak, PhD; Chan Wang, PhD; Tamas Gonda, MD; Paul Oberstein, MD; and Huilin Li, PhD.

Other study co-investigators include Mykhaylo Usyk, PhD, at Albert Einstein College of Medicine in New York City; Neal Freedman, PhD, and Wen-Yi Huang, PhD, at the National Cancer Institute in Rockville, Maryland; and Caroline Um, PhD, at the American Cancer Society in Atlanta.

In the march of metastasis, a molecular trail of crumbs guides some cancer cells from the primary tumor to establish new colonies within the body. Blocking the cells’ ability to follow the trail might halt metastasis but could also meddle with an intricate cellular signaling system critical to immune response. Purdue University scientists are deciphering this signaling system to better understand how it could be used to address multiple diseases, including cancer.

Recent work, published in Nature, focused on a specific transaction inside the cell but is broadly applicable to how cells respond to signals from the endocrine system, a hormonal messaging system that influences metabolism, growth and reproduction and helps the body maintain homeostasis.

“There are multiple pathways inside a cell that are triggered by this messaging system and when they don’t work together properly, it promotes disease,” said research lead John Tesmer, the Walther Distinguished Professor in Cancer Structural Biology in the College of Science and a member of the Purdue Institute for Cancer Research. “Some of these pathways are useful, so ideally, we shouldn’t just turn off the signal at the source. But maybe we can find compounds that elicit a more nuanced response inside the cell, such as by preserving good pathways and dampening those that are bad.”

Tesmer’s work is part of Purdue’s presidential One Health initiative, which involves research at the intersection of human, animal and plant health and well-being.

When cells in the body are threatened by pathogens or tissue damage, they secrete chemokines — small proteins that summon immune cells to move toward the source of the signal. As chemokines encounter cells, they bind to a receptor that spans the cell membrane, which triggers a response inside the cell. Ordinarily, these triggered receptors are gradually pulled into the cell, a mechanism that ensures a cell can respond to changes in the amount of chemokine in its environment.

Tesmer’s team studied one such receptor, atypical chemokine receptor 3 (ACKR3), which is part of a much larger class of G protein-coupled receptors (GPCRs) that stud the surface of animal, plant and fungi cells, allowing these cells to sense their environment.

GPCRs are an attractive target for drug discovery because drugs need only bind to the cell surface receptor, without entering the cell, to effect a change inside the cell. By some estimates, more than 30% of drugs approved by the Food and Drug Administration target GPCRs. While many drugs take advantage of the receptors, they function as part of a vast sequence of molecular steps that isn’t fully understood. ACKR3 offers a good example of the complexity of the system and the potential rewards of decoding it. 

ACKR3 can be thought of as a flexible tube of protein that weaves its way through the cell membrane seven times to make a barrel-shaped bundle. One end of the barrel protrudes out of the cell while the other is inside. The ends form pockets to which molecules or proteins can bind. A chemokine binding to the outer pocket of ACKR3 changes the shape of the inner pocket. Like ringing a doorbell, this change in conformation activates the receptor, calling for attention from within.

A series of steps inside the cell answers the call, and with each come options that can prompt a different cellular response from the same activated receptor. First, a protein from the GPCR kinase (GRK) family arrives and attaches phosphate molecules to molecular tails dangling from the inner end of the bundle. The pattern of phosphates, known as a “barcode,” can depend on which GRK protein answers the call. The barcode in turn influences the next step, in which a protein from the so-called arrestin family binds to the barcode, cuing the cell’s response.

During metastasis, some cancer cells produce excess ACKR3 receptors that allow them to more easily follow the trail of chemokines to distant organs for colonization. With a better understanding of what happens after ACKR3 is activated, it might be possible to control this process in cancerous cells without hampering how the immune system responds to infection.

In the Nature paper, the team looked at the barcodes installed by two different GRKs, GRK2 and GRK5, into ACKR3 and how they affect the interactions of two different arrestins, arrestin2 and arrestin3, with the receptor. For each combination, they obtained structural data for the configurations formed with ACKR3 using cryogenic electron microscopy.

And indeed, both the barcode and the arrestin mattered. GRK2 puts its barcode near the ends of the molecular tails on the receptor pocket creating a loose, dynamic binding site for the arrestins, whereas GRK5 put its barcode closer to the pocket of the receptor, prompting a tight, more rigid interaction between the arrestins and ACKR3. Because arrestin3 is unable to bind to the cell surface like arrestin2, it also results in more dynamic interactions. These differences can readily be detected by signaling machinery inside the cell.

“We’re trying to get at the reason why it matters which GRK is putting the barcodes in. In particular, is there anything there that would help us understand how they differentially engage downstream machinery?” Tesmer said. “And what we found is that, for ACKR3, it’s not so much the barcode sequence itself that matters, it’s the region, the location of the barcode that matters more in terms of the arrestin-receptor configuration. This emphasizes the amazing complexity of signaling that can occur after triggering just a single receptor but also represents an opportunity for researchers to devise therapeutic approaches that might shut down one set of barcode-specific pathways but preserve others that are beneficial.”

Reference: Chen Q, Schafer CT, Mukherjee S, et al. Effect of phosphorylation barcodes on arrestin binding to a chemokine receptor. Nature. 2025;643(8070):280-287. doi: 10.1038/s41586-025-09024-9

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