In December, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and the Sheba Medical Center, part of Israel’s Ministry of Health, signed a Memorandum of Understanding to further infectious disease research collaborations between U.S.-funded and Israel-funded scientists. Signers of the agreement were Anthony S. Fauci, M.D., director of NIAID, and Yitshak Kreiss, M.D., director general of the Sheba Medical Center. 

The partnership grew out of a need for more cooperation in biomedical research, a critical part of preparing for the next pathogen of pandemic or endemic potential. The memorandum represents the continuation of the existing relationship between NIAID’s Vaccine Research Center (VRC) in Bethesda, Md., and Sheba Medical Center. 

Daniel Douek, M.D., Ph.D., chief of the VRC’s Human Immunology Section traveled to Israel to meet with representatives of Sheba and celebrate the opening of the Sheba Pandemic Preparedness Research Institute (SPRI). 

 “What this does is to formalize the relationship between our two organizations, not just legally so that we can exchange ideas and exchange materials and project intellectual property, but it formalizes the relationship at an intergovernmental level,” Douek said. “We’re already collaborating. We’ve been collaborating for a few years on COVID-19 and other projects.” 

A joint study published recently in Nature Communications found common immune responses in people infected with different SARS-CoV-2 variants, which may explain why COVID-19 vaccines against older variants continue to be effective against newer variants. 

Studies, consistent exchanges of research and scientific materials, and routine visits by scientists to both organizations will continue under the agreement. 

“Sheba needs the NIH, and the NIH needs Sheba for the future benefit of humanity,” Douek said.

To reduce the spread of HIV infection, the World Health Organization (WHO) recommends pre-exposure prophylaxis (PrEP) in populations with an annual HIV infection incidence greater than 3%. Given that the annual HIV incidence in Uganda is estimated at 0.40% (0.46% among females and 0.35% among males), there are people who may have a higher HIV risk and may benefit from PrEP but are not targeted for services. To further reduce the spread of HIV in Uganda, researchers used results from three survey rounds of HIV-negative participants within the Rakai Community Cohort Study (RCCS) to estimate the prevalence of high-risk individuals eligible for PrEP within the general population and the incidence of HIV infection associated with eligibility. 

In this study, a subset of questions from Uganda’s PrEP eligibility tool that are routinely asked within the RCCS surveys were used to determine PrEP eligibility. Eligibility was defined as reporting at least one of the following HIV risk behaviors in the past 12 months: sexual intercourse with more than one partner of unknown HIV status; nonmarital sex act without a condom; sex engagement in exchange for money, goods, or services; or experiencing genital ulcers. HIV incidence was estimated by analyzing seroconversion from HIV-negative to HIV-positive in participants who contributed to at least two of the survey rounds.

Overall, 29% of participants in the analysis met the eligibility criteria. Of these, 22% reported one HIV risk, 6% reported two HIV risks, and 1% reported three HIV risks. The results showed that PrEP eligible participants had twice the risk of acquiring HIV than their non-eligible counterparts. Furthermore, risk increased threefold in uncircumcised males but not circumcised males. Additionally, men who reported higher prevalence of risky behaviors had lower increase in HIV incidence compared to women, likely due to circumcision status and higher antiretroviral therapy coverage in HIV-infected females, leading to a decrease in transmission to men. The findings of this study support the use of PrEP eligibility screening in general populations with HIV incidence lower than 3% to reduce HIV acquisition even further in these populations.

Reference: Ssempijja et al. High Rates of Pre-exposure Prophylaxis Eligibility and Associated HIV Incidence in a Population With a Generalized HIV Epidemic in Rakai, Uganda, JAIDS Journal of Acquired Immune Deficiency Syndromes, July 1, 2022 - Volume 90 - Issue 3 - p 291-299.

Antiretroviral treatment is vital for suppression of HIV replication in pregnant women living with HIV and to prevent mother-to-child transmission. Currently, tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral drugs is recommended for use in pregnant women and has been prescribed for several years. A newer related drug, tenofovir alafenamide (TAF), is approved for use in multiple antiretroviral regimens to treat non-pregnant adults and has an improved safety profile in this population. However, little is known about how the physiological changes during pregnancy impact the pharmacokinetics of this drug to support its use as a treatment option.

The goal of this study was to characterize the pharmacokinetics of TAF during pregnancy and postpartum to ensure drug concentrations are maintained at a therapeutic level and address maternal and infant clinical outcomes. Between 2016 – 2018, a total of 58 pregnant women from the United States participated in this study and were given one of two TAF-containing drug regimens. Comprehensive pharmacokinetic assays were conducted during the second and/or third trimesters as well as 6 – 12 weeks postpartum. Blood samples, maternal plasma, cord blood (at delivery), and infant washout samples were also collected. 

While the TAF pharmacodynamics between the two groups of pregnant women in this study differed, both groups had drug exposures within the same range as non-pregnant women with HIV.  At delivery, over 90% of women had HIV viral loads suppressed below 400 copies/mL, and no mother-to-child HIV transmissions occurred. Additionally, TAF was well tolerated by mothers in this small study. Taken together, these results suggest that larger studies on the use of TAF-containing drug regimens in pregnant women with HIV should be pursued to determine if they are a safe and effective option for more widespread use. 

Reference: Brooks et al. Pharmacokinetics of tenofovir alafenamide with and without cobicistat in pregnant and postpartum women living with HIV: Results from IMPAACT P1026s, AIDS: March 1, 2021 - Volume 35 - Issue 3 - p 407-417.

Certain species of fungi are responsible for many common infections including yeast infections, ringworm, thrush, and athlete’s foot. While these diseases may not lead to serious outcomes for most healthy individuals, fungal infections can be deadly, especially for patients with weakened immune systems. One fungal pathogen, Candida auris, is an emerging healthcare-associated infection of growing public health concern. The first case of Candida auris was reported in 2009 in Japan, where it was isolated from a patient’s ear (Auris is Latin for “ear”). Outbreaks have since emerged rapidly around the globe. In the United States, C. auris infections have been increasing over the past few years, with more than 1460 cases reported in 2021. C. auris is typically found in hospitals and other healthcare settings and can cause serious bloodstream and wound infections.

Like other Candida species, C. auris is a type of yeast. However, unlike its yeasty cousins, this pathogen can colonize patients’ skin and persist for long periods of time on environmental surfaces. Another challenge is that C. auris is often resistant to one or more of the major classes of drugs that are typically used to treat fungal infections. While most C. auris infections can be treated with a class of antifungals called echinocandins, resistance to these drugs has also been reported, making some infections difficult to treat. C. auris is the only fungal pathogen identified as an ‘urgent’ threat in CDC’s Antibiotic Resistance Threat Report.

Back to basics

NIAID supports several researchers who are asking fundamental questions about the biology of C. auris. Today’s NIAID Now post features insights from NIAID-funded researchers, Jeniel Nett, M.D., Ph.D., associate professor of medicine and medical microbiology and immunology at University of Wisconsin-Madison, and Christina Cuomo, Ph.D., associate director of the Genomic Center of Infectious Diseases at the Broad Institute of Massachusetts Institute of Technology and Harvard University.

How is C. auris able to colonize the skin and persist in the environment?

C. auris can live and grow on the skin or in the body without causing illness. However, people who are colonized with C. auris may spread the pathogen to others and are at risk of getting sick later on if they develop infections. One important question to understanding C. auris outbreaks is: how is the fungus able to colonize skin so effectively and to persist in the environment? Dr. Nett’s research group is tackling this question by studying C. auris growth in the lab using two different systems. The first is designed to mimic human sweat and skin. Nett noted, “we think that this represents skin to some degree but also when surfaces get contaminated with skin and sweat components.” The other system is pig skin. “Pigs have similar skin to humans in terms of skin thickness and some of the cell types,” Nett explained. Using these systems, Nett and colleagues have shown that C. auris is able to readily grow on skin. “It really seems to mirror what we’re seeing patients,” said Nett. They’ve found that when the fungus is grown in the synthetic sweat medium, it forms multi-layered plaques, or biofilms, both on the pig skin as well as on hard surfaces. Compared to other Candida species, the biofilms are thicker and contain more viable organisms. C. auris biofilms can also persist on surfaces without drying out for up to two weeks in the lab.

Jeniel Nett, M.D., Ph.D., associate professor of medicine and medical microbiology and immunology at University of Wisconsin-Madison

Credit: Dr. Jeniel Nett

Nett’s research demonstrates the ability of the fungus to colonize skin and form persistent biofilms on environmental surfaces, which has implications for transmission in healthcare settings. “This really becomes important with reusable medical equipment that goes room to room,” Nett emphasized. The systems Nett’s group has developed to study C. auris in the lab can also inform potential strategies to remove C. auris from the skin of patients. Nett’s research has shown that while antiseptics are somewhat effective, they are not as active against C. auris when the fungus is growing in the skin environment compared to when it is growing without the skin present. In a published manuscript, Nett and colleagues demonstrated that the commonly used topical antiseptic chlorhexidine does not fully remove C. auris from the skin of patients. They also showed that by adding isopropanol, as well as some essential oils, including tea tree and lemongrass, to chlorhexidine, they were able to improve the activity of the antiseptic. Her group is still investigating what specific components of skin and sweat are triggering biofilm growth in C. auris. Understanding this could lead to better, more specific strategies to disrupt skin colonization.

How did C. auris outbreaks emerge around the world, and how has the fungus become multidrug-resistant?

Soon after it was first identified, outbreaks of C. auris arose in four distinct locations—South Asia, East Asia, Africa, and South America—nearly simultaneously. Dr. Cuomo and colleagues are using a genomics approach to better understand this phenomenon. 
“One fundamental question genomics can answer is, what has been the history of the pathogen over time?” Cuomo explained. “We can take isolates from different patients, and by comparing them we can infer back in time to where they have a common connection.”

Christina Cuomo, Ph.D., associate director of the Genomic Center of Infectious Diseases at the Broad Institute of Massachusetts Institute of Technology and Harvard University

Credit: Dr. Christina Cuomo

Together with colleagues at the Centers for Disease Control and Prevention, Cuomo’s group helped confirm that the different outbreaks were caused by distinct genetic groups, or ‘clades.’ As cases have continued to spread around the globe, researchers have been able to trace new C. auris isolates back to these four major clades, allowing them to understand how the different outbreaks are connected.

Expanding on this initial work, Cuomo’s group is looking more closely at the different C. auris clades and identifying key genetic differences both within and between these groups as well as among C. auris and other related Candida species. From this analysis, they have generated hypotheses about which genes in the fungus are important for contributing to disease in humans. Such studies provide important insight into the biology of C. auris and can help identify potential targets for new drugs.

Researchers are also actively trying to understand how this fungal species has evolved to become resistant to certain antifungal drugs. Combining clinical data and experimental evolution studies, Cuomo’s group has identified specific mutations, or genetic changes, contributing to resistance to the major classes of antifungal drugs, including echinocandins. Cuomo explained that a single change in one of the C. auris proteins causes the fungus to go from sensitive to resistant, which explains why patients will sometimes stop responding in the middle of treatment with echinocandins.

The genomic resources that Cuomo and her group have developed are used by public health laboratories to help assess the frequency of drug resistance in C. auris. Understanding what genetic changes are associated with drug resistance can also help inform patient treatment. “That’s the kind of information we want to be marrying to traditional diagnostics, to think about how can we best type resistance across the course of a patient’s treatment,” Cuomo noted. “We know that resistance can arise while on treatment. We’d like to detect that as soon as it emerges, and not when the patient succumbs to a very high fever or other devastating symptoms.”

From knowledge to solutions

Working on a novel pathogen is a challenging effort. Both Drs. Nett and Cuomo have forged into relatively new scientific territory, and have had to develop new tools, methods, and resources to study C. auris. However, their work has the potential to make a significant impact against this emerging disease. While the scientific questions they both are tackling are fundamental in nature, the answers are of critical importance to patient care and public health interventions.

Learn more about this research by reading recent papers from Dr. Nett, Dr. Cuomo, and colleagues:

CJ, Johnson et al. Modeling Candida auris skin colonization: Mice, swine, and humans. PLOS Pathogens. DOI: 10.1371/journal.ppat.1010730 (2022)

JM Rybak et al. In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris. Clin Microbiology Infect. DOI:10.1016/j.cmi.2021.11.024 (2022). 

C Johnson et al. Augmenting the Activity of Chlorhexidine for Decolonization of Candida auris from Porcine skin. J Fungi. DOI: : 10.3390/jof7100804 (2021).

J Muñoz et al. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics. DOI: : 10.1093/genetics/iyab029 (2021). 

N Chow et al. Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses. mBio. DOI: : 10.1128/mBio.03364-19 (2020). 

M Horton et al. Candida auris Forms High-Burden Biofilms in Skin Niche Conditions and on Porcine Skin. mSphere. DOI : 10.1128/mSphere.00910-19 (2020).

S Lockhard et al. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis. DOI: 10.1093/cid/ciw691 (2017) 

Eix EF, CJ Johnson, KM Wartman, JF Kernien, JJ Meudt, D Shanmuganayagam, ALF Gibson, JE Nett. 2022. Ex vivo human and porcine skin effectively model C. auris colonization, differentiating robust and poor fungal colonizers. J Infect Dis. PMID: 35267041

The National Institutes of Health has awarded approximately $34 million annually over the next five years to fund six independent Centers for HIV Structural Biology. The National Institute of Allergy and Infectious Diseases (NIAID) committed approximately $30 million in funding, with an additional $4 million from the NIH Office of AIDS Research.

The Centers program, established in 2007 by the National Institute of General Medical Sciences (NIGMS), was transitioned to NIAID in 2019 as part of the transfer of the NIGMS HIV/AIDS portfolio to the NIAID Division of AIDS (DAIDS). Last year, NIAID solicited applications to RFA AI-21-030: Centers for HIV Structural Biology using the U54 specialized center funding mechanism. The U54 mechanism was utilized to allow enhanced NIAID program oversight and encourage the involvement of NIH intramural researchers. The new Centers largely maintained the structure of the existing Centers while refocusing on research topics that support NIAID priorities of HIV prevention, therapy and cure. In addition, a new Developmental Core was added to foster mentoring and training of young scientists in HIV research.

The Center researchers integrate techniques from structural biology, biochemistry and cell biology to capture in unprecedented detail the three-dimensional structures of HIV proteins and nucleic acids and their interactions with cellular components. This information provides an entirely new perspective on HIV infection and immune control that helps elucidate how the different components interact and reveal new approaches for disrupting those interactions, potentially leading to new targets for HIV therapies and preventative vaccines. In total over 300 scientists from dozens of institutions in the US and abroad will participate in the studies put forward by the Centers. 

The six applications selected for funding include research across the HIV life cycle, aiming, for example, to elucidate the mechanism the HIV envelope protein uses to enter a target cell, the interactions of virus structures with host proteins that either facilitate or antagonize infection, and the way that the HIV RNA genome folds into complex assemblies with other viral components before being packaged into newly formed virions.

The following awardees will receive the indicated funds annually for five years: 

Duke University

Duke Center for HIV Structural Biology (DCHSB)

Director: Priyamvada Acharya

Award: $5.5 million

Seattle Children’s Hospital

Behavior of HIV in Viral Environments (B-HIVE)

Co-Directors: Bruce Torbett, Stefan Sarafianos

Award: $6.3 million 

University of California, San Francisco

HIV Accessory and Regulatory Complexes (HARC)

Director: Nevan Krogan

Award: $5.7 million

University of Michigan

Center for Structural Biology of HIV RNA (CRNA)

Director: Alice Telesnitsky

Award: $5.5 million

University of Pittsburgh

Pittsburgh Center for HIV Protein Interactions (PCHPI)

Directors: Angela Gronenborn, Tatyana Polenova

Award: $5 million

University of Utah

Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics (CHEETAH)

Director: Wesley Sundquist

Award: $5.5 million