This blog is adapted and cross-posted from HIV.gov.

The Department of Health and Human Services Guidelines Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (the Panel) has developed recommendations for the use of statin therapy in people with HIV, in collaboration with representatives from the American College of Cardiology, the American Heart Association, and the HIV Medicine Association. The new guidelines, Recommendations for the Use of Statin Therapy as Primary Prevention of Atherosclerotic Cardiovascular Disease in People with HIV, were published on February 27, 2024, and can be found online at ClinicalInfo.hiv.gov.

Findings from Large Clinical Trial Informed New Statin Guidelines

The new guidelines were informed by findings from the NIH-supported Randomized Trial to Prevent Vascular Events in HIV or REPRIEVE trial. REPRIEVE found that a statin (pitavastatin), a cholesterol-lowering medication, may offset the high risk of cardiovascular disease in people living with HIV by more than a third, potentially preventing one in five major cardiovascular events (e.g., heart attacks, strokes, or surgery to open a blocked artery) or premature deaths in this population. The study findings were published in the the New England Journal of Medicine last summer. The Panel and representatives of the three professional medical societies translated those research findings into the clinical practice guidelines published this week.

HIV.gov discussed findings from the REPRIEVE trial in some of our video conversations from last summer’s IAS Conference on HIV Science. Watch Carl Dieffenbach, director of NIAID's Division of AIDS, and the study’s principal investigator Steven Grinspoon discuss the REPRIEVE Study.

Recent arbovirus outbreaks – specifically dengue, chikungunya, and Zika in the Americas – led NIAID and the Instituto de Medicina Tropical “Pedro Kouri” in Cuba to co-host a joint scientific meeting on Addressing Global Health Challenges Through Scientific Innovation and Biomedical Research. The meeting was held Feb. 14-16 in Havana.

The arbovirus cases, atop the COVID-19 pandemic, are reminders that emerging and re-emerging infectious diseases can quickly become research priorities and pose global health threats.

Though infectious disease was prominent in conference discussions, the scientific agenda sought to highlight biomedical research areas of mutual and global priority. These topics are becoming increasingly interconnected in the U.S. and worldwide. As such, the conference brought together researchers to review current science and discuss ways to develop effective interventions to control epidemics in the Americas and globally. 

The bilateral technical scientific research meeting convened subject matter experts on infectious and non-communicable diseases, including arboviruses, pandemic preparedness, cancer, neurological disorders, and long-term health concerns. The agenda also included cross-cutting biomedical research areas, such as immunology, genomics, and precision medicine.

The Cuban Academy of Sciences (ACC) provided a meeting highlight by honoring two U.S. scientists for their longstanding and innovative contributions to global arbovirus and neurological disorders research. Each scientist was granted the designation of Corresponding Academic to the ACC.

Scientists Identify Interferon-gamma as Potential SARS-CoV-2 Antiviral

Conditioning the lungs with interferon-gamma, a natural immune system protein (cytokine) best known for fighting bacterial infections, appears to be a strong antiviral for SARS-CoV-2, according to National Institutes of Health scientists and colleagues. Their new study, published in Nature Communications, shows in two different mouse models that when a bacterial infection triggers the release of interferon-gamma in the lungs, those animals subsequently are protected from infection by SARS-CoV-2, the virus that causes COVID-19. The investigators further report that using recombinant interferon-gamma in the nose of study mice at the time of viral exposure substantially reduces SARS-CoV-2 infection and COVID disease.

The lead project scientists suggest testing interferon-gamma further, alone and in combination with other treatments, to limit early SARS-CoV-2 infection in people. They also hypothesize that people with prior bacterial infections that naturally release interferon-gamma in their lungs may be less susceptible to COVID-19.

NIH’s National Institute of Allergy and Infectious Diseases (NIAID) led the project with collaborators at Malaghan Institute of Medical Research in New Zealand.

Previously, the research team had observed that a vaccine for tuberculosis, known as BCG, given intravenously to establish a mild lung infection subsequently provided strong protection against SARS-CoV-2 challenge. The new study reveals that interferon-gamma, released by the immune system in response to BCG vaccine, is required for the observed SARS-CoV-2 antiviral immunity. The investigators also examined the mechanism by which interferon-gamma protects against SARS COV-2 and presented evidence that the cytokine targets lung epithelial cells, a major site of early viral replication, thus limiting its spread.

When the project began, the research team did not expect interferon-gamma to be the necessary component for SARS-CoV-2 protection. Traditionally, other forms of interferon – alpha, beta and lambda – are known to fight viruses, but not gamma. Their findings thus uncover a newly appreciated anti-viral function for this cytokine.

References:

K Hilligan, et al. Bacterial induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2. Nature Communications. DOI: 10.1038/s41467-023-43447-0 (2023).

K Hilligan, et al. BCG mediated protection of the lung against experimental SARS-CoV-2 infection. Frontiers in Immunology. DOI: 10.3389/fimmu.2023.1232764 (2023).

K Hilligan, et al. Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge. Journal of Experimental Medicine. DOI: 10.1084/jem.20211862 (2022).

NIAID Team Explores Metabolism in Determining Infection Severity

Some pathogens can cause infectious disease by following several different paths into a host, and disease severity can vary depending on the infection route used. This raises research questions about how the route that a pathogen uses influences infection. Francisella tularensis, the bacterium that causes the disease tularemia – also called rabbit fever – can infect a person in many ways:

•    In the lungs by breathing
•    In the skin from a bite or handling infected animals
•    In the eye by airborne exposure
•    In the gut by consuming contaminated food or water

Consistently, the most severe tularemia cases involve lung infections, sometimes leading to death. Fortunately, antibiotics are available to treat tularemia – though early treatment can be challenging because the disease is difficult to diagnose. There are about 200 cases of tularemia reported in people each year in the United States.

Curious to understand why cases of tularemia in the lung – in contrast to those that start in the skin – can be so severe, NIAID scientists compared mice infected with the same F. tularensis dose in the nasal passage (to establish disease in the lung) to mice infected in the skin. They then compared tissue in diseased areas for immune and metabolic responses to find out if the mice were fighting the infection, how, and whether tweaking the responses can influence the outcome.

Their findings, published in the science journal PLOS One, show that the bacterium is “exquisitely adept” at manipulation, delaying the immune response in the lungs to create an environment for greater infection and replication. For mice infected in the skin, symptoms – such as swollen glands – appeared faster, thus triggering timely immune protection.

The research team, at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, thinks the findings could extend beyond F. tularensis to other pathogens. For example, Yersinia pestis, the bacterium that causes plague, also is transmitted by numerous routes that manifest most severely in the lungs.

“Our hypothesis is that the programmed anti-inflammatory and pro-resolving nature of the lung is exploited by pathogens, resulting in more severe and lethal disease,” study senior investigator Catharine Bosio, Ph.D., explained. “The metabolic environment in the skin is prone to mounting a faster inflammatory response, resulting in better control early in infection.”

By understanding the metabolic role in infection, researchers can better understand and predict which therapeutic approaches could be successful. For example, in the study the team hypothesized that manipulating the lung to be more inflammatory would help control F. tularensis early on.

“However, it had the opposite effect,” Dr. Bosio said. “Now we know that promoting that type of metabolic response may not be a good intervention and may actually harm the host.”

In future studies the group plans to identify how different components of pathogens like F. tularensis affect host metabolic responses and response to infection.

Reference:
F Jessop et al. Route of Francisella tularensis infection informs spatiotemporal metabolic reprogramming and inflammation in mice. PLOS One. DOI: 10.1371/journal.pone.0293450.

Following a peak in the summer of 2022, new infections in the mpox clade IIb outbreak have decreased, due in part to the rapid availability and uptake of vaccines and other preventive measures. However, mpox remains a health threat, and no treatment has been proven safe and effective for people experiencing mpox disease.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, launched the STOMP trial to determine whether the antiviral drug tecovirimat can safely and effectively treat mpox. Tecovirimat, also known as TPOXX, was initially developed and approved by the Food and Drug Administration to treat smallpox—a species of virus closely related to mpox—but the drug’s safety and efficacy as an mpox treatment has not been established. The STOMP trial is a phase 3 study that aims to enroll about 500 people—a process that may require considerable time while mpox burden is low in study countries. NIAID continues to prioritize this study even while case counts are low.

VIDEO: Cyrus Javan of NIAID’s Division of AIDS explains the importance of the STOMP trial (audio description version here):

The STOMP trial was designed to be as inclusive as possible to ensure study results provide information on how tecovirimat works in the diverse populations affected by mpox. The trial is enrolling adults and children of all races and sexes, people with HIV, and pregnant and lactating people across 60 sites in the United States and Mexico, with an option for remote enrollment from other U.S. locations. More sites are expected to open in East Asia and South America.

The mpox virus has been endemic—occurring regularly—in west, central and east Africa since the first case of human mpox disease was identified in 1970. Mpox can cause flu-like symptoms and painful blisters or sores on the skin. People who acquire mpox tend to clear the infection on their own, but the virus can cause serious disease in children, pregnant people, and other people with compromised immune systems, including individuals with advanced HIV disease. Rare but serious complications of mpox include dehydration, bacterial infections, pneumonia, brain inflammation, sepsis, eye infections and death.

Completing the STOMP trial is essential, not only to evaluate a therapeutic option for the current mpox outbreak, but also to guide preparation for future outbreaks and provide evidence that could inform medical practice in historically endemic countries. The STOMP trial is sponsored by NIAID and led by the NIAID-funded Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG).

Beyond STOMP, NIAID is co-sponsoring the PALM007 trial of tecovirimat as treatment for clade I mpox in the Democratic Republic of the Congo (DRC) with the DRC’s National Institute of Biomedical Research. PALM007 is actively enrolling. In addition, NIAID is sponsoring an immunogenicity study of the JYNNEOS preventive vaccine, which has completed enrollment and is expected to report initial results in 2024. More information about these studies, including enrollment in STOMP and PALM007, is available here:

STOMP tecovirimat treatment study 
PALM007 tecovirimat treatment study
JYNNEOS vaccine study