NIH officials assess threat of H5N1

Balancing enhanced vigilance and “business as usual”

Highly pathogenic H5N1 avian influenza A virus (HPAI H5N1) remains a low risk to the general public, and public health experts in the United States believe that available treatments and vaccines, as well as those in development, are sufficient to prevent severe disease. However, the National Institutes of Health (NIH) and its federal partners remain focused on monitoring the virus and evaluating changes, according to leading officials at the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH.

In a commentary published in the New England Journal of Medicine, NIAID Director Jeanne M. Marrazzo, M.D., M.P.H., and Michael G. Ison, M.D., M.S., chief of the Respiratory Diseases Branch in NIAID’s Division of Microbiology and Infectious Diseases, say people should find a balance between enhanced vigilance and “business as usual” with respect to HPAI H5N1.

Since 1996, HPAI H5N1 influenza viruses have circulated in at least 23 countries. In late 2021, HPAI H5N1 spread from Europe to North America causing sporadic infections among wild birds and poultry farms. In 2022, the virus spread to South America where it devastated birds and marine mammals. In March 2024, USDA scientists identified HPAI H5N1 in U.S. dairy cows, and it subsequently reached herds in 16 states. The virus has been detected in dairy herds in three states over the past 30 days, according to USDA/APHIS. In 2024, the virus has caused 66 confirmed and 7 probable cases of influenza in people in the U.S. and one case in Canada. These human cases have been caused by either the H5N1 type circulating in birds (D1.1) or the type circulating in dairy cows (B3.13).

Against this backdrop, Drs. Marrazzo and Ison say there are four keys to controlling the current outbreak. The first imperative is timely, effective collaborations among investigators in human and veterinary medicine, public health, health care, and occupational workers, such as dairy and poultry workers.

This involves cultivating trust not only between numerous entities, but with people seeking care for symptoms of concern, including conjunctivitis, the authors write. Fortunately, so far most U.S. cases of HPAI H5N1 have been mild and resolved on their own without the need for treatment.

Their second key is a focus on the Canadian HPAI H5N1 patient, who developed respiratory failure and required life-saving medical intervention and treatment before recovering. The authors write that mutations found in the virus in this patient highlight an urgent need for vigilant disease surveillance to identify and assess viral changes to evaluate the risk for person-to-person transmission. Effective surveillance, they say, requires that complete genomic sequencing data from animals and people are made rapidly and readily available.

Without information pertaining to where and when isolates were collected, the data cannot be linked phylogenetically to other reported sequences, limiting insight into how the virus is spreading, they write. These data would also provide opportunity for early detection of mutations that might portend avidity for human respiratory epithelium, which may require as little as one mutation in the virus.

Third, researchers must continue to develop and test medical countermeasures—such as vaccines and therapies that eliminate or alleviate disease—against H5N1 and other influenza viruses. Fortunately, current vaccine candidates neutralize the circulating strains, which so far are susceptible to antivirals that could mitigate transmission and severity of illness, they write.

Lastly, Drs. Marrazzo and Ison encourage people to take precautions to prevent exposure to the virus and minimize the risk of infection. For example, people who work with poultry and cows should use personal protective equipment and educate themselves about occupational risks when working with birds and mammals, as CDC and USDA have repeatedly recommended.

Ideally, following these four steps will help scientists and public health officials investigating HPAI H5N1 to answer the many remaining questions more quickly about how the virus is spreading, evolving, and affecting people, other mammals, and birds.

Photo of a wild bird. To the right is a colorized transmission electron micrograph of H5N1 virus particles (purple). H5N1 bird flu is widespread in wild birds worldwide, and in 2024 is causing a multistate outbreak in poultry and U.S. dairy cows. Bird photo by NIAID; micrograph, which has been repositioned and recolored by NIAID, is courtesy CDC. Picture Credits: NIAID and CDC

Bibliographic information:
M Ison and J Marrazzo, The Emerging Threat of H5N1 to Human Health, NEJM (2024), DOI: 10.1056/NEJMe2416323

Press release from the National Institute of Allergy and Infectious Diseases – NIH

Keep Reading

Enzyme that protects against viruses could fuel cancer evolution

An enzyme that defends human cells against viruses can help drive cancer evolution towards greater malignancy by causing myriad mutations in cancer cells, according to a study led by investigators at Weill Cornell Medicine. The finding suggests that the enzyme may be a potential target for future cancer treatments.

In the new study, published Dec. 8 in Cancer Research, scientists used a preclinical model of bladder cancer to investigate the role of the enzyme called APOBEC3G in promoting the disease and found that it significantly increased the number of mutations in tumor cells, boosting the genetic diversity of bladder tumors and hastening mortality.

“Our findings suggest that APOBEC3G is a big contributor to bladder cancer evolution and should be considered as a target for future treatment strategies,”

said study senior author Dr. Bishoy M. Faltas, assistant professor of cell and developmental biology at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.

The APOBEC3 family of enzymes is capable of mutating RNA or DNA—by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an erroneous nucleotide at that position. The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV—they attempt to hobble viral replication by mutating the cytosines in the viral genome.

The inherent hazardousness of these enzymes suggests that mechanisms must be in place to prevent them from harming cellular DNA. However, starting about a decade ago, researchers using new DNA-sequencing techniques began to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the mutations in these tumors were APOBEC3-related—and that these mutations appeared to have a role in helping tumors evade the effects of chemotherapy.

Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations needed for cancerous growth but also boost their ability to diversify and “evolve” thereafter—enabling further growth and spread despite immune defenses, drug treatments, and other adverse factors.

In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all the knockout-only mice survived, whereas nearly a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in the mouse cells was present in the nucleus, where cellular DNA is kept using an ‘optical sectioning’ microscopy technique. Previously, this protein had been thought to reside only outside the nucleus. They also found that the bladder tumors of the APOBEC3G mice had about twice the number of mutations compared to the tumors in knockout-only mice.

Identifying the specific mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had caused a greater mutational burden and genomic diversity in the tumors, likely accounting for the greater malignancy and mortality in the APOBEC3G mice.

“We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from signatures caused by other members of the APOBEC3 family” said Dr. Liu.

Lastly, the researchers looked for APOBEC3G’s mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are linked to worse outcomes.

“These findings will inform future efforts to restrict or steer tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Faltas.

Press release from Weill Cornell Medicine

Keep Reading