Selected Grantee Publications
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- Infectious Diseases
- Imaging
Structures of Respiratory Syncytial Virus G Bound to Broadly Reactive Antibodies Provide Insights into Vaccine Design
Juarez et al., Scientific Reports. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11906780
Respiratory syncytial virus (RSV) is one of the leading causes of severe lower respiratory infection in both infants and older adults. RSV viral entry and modulation of the host immunity is mediated by attachment glycoprotein RSV G binding to the chemokine receptor CX3CR1. Antibodies isolated from RSV-exposed individuals have shown great promise in host protection. Researchers using an ORIP-funded electron microscope, in conjunction with X-ray crystallography, have solved the structure of these antibodies bound to the RSV G protein and identified a novel dual antibody binding region. The presence of dual antibody binding sites indicates the potential to elicit antibody responses that resist virus escape. These findings will help develop next-generation RSV prophylactics and provide insight for new concepts in vaccine design. Supported by ORIP (S10OD027012, S10OD025097), NIAID, NHGRI, and NIGMS.
Liver-Specific Transgenic Expression of Human NTCP In Rhesus Macaques Confers HBV Susceptibility on Primary Hepatocytes
Rust et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937851
This study establishes the first transgenic nonhuman primate model for hepatitis B virus (HBV). Male and female rhesus macaques were engineered to express the human HBV receptor, NTCP (hNTCP), specifically in the liver. Researchers used PiggyBac transposon technology to introduce a liver-specific NTCP transgene into embryos, which were then implanted into surrogate females. The resulting offspring expressed hNTCP in hepatocytes and demonstrated high susceptibility to HBV infection. This model overcomes the species-specific limitations of HBV research, providing a powerful tool for studying HBV biology and evaluating HBV treatments in a clinically relevant model system. Supported by ORIP (P51OD011092), NIDA, and NIAID.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
Indoleamine-2,3-Dioxygenase Inhibition Improves Immunity and Is Safe for Concurrent Use with cART During Mtb/SIV Coinfection
Singh et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39114981/
HIV and tuberculosis (TB) coinfection can lead to TB reactivation that is caused by chronic immune system activation. Researchers explored indoleamine-2,3-dioxygenase (IDO) inhibition as a host-directed therapy (HDT) to mitigate immune suppression and TB reactivation in a rhesus macaque Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) model. The IDO inhibitor D-1-methyl tryptophan improved T-cell immunity, reduced tissue damage, and controlled TB-related inflammation without interfering with the efficacy of combinatorial antiretroviral therapy (cART). These findings support IDO inhibition as a potential HDT in HIV/TB coinfection, providing a strategy to balance immune control while preventing TB reactivation in cART-treated patients. Supported by ORIP (S10OD028732, U42OD010442, S10OD028653) and NIAID.
Transiently Boosting Vγ9+Vδ2+ γδ T Cells Early in Mtb Coinfection of SIV-Infected Juvenile Macaques Does Not Improve Mtb Host Resistance
Larson et al., Infection and Immunity. 2024.
https://pubmed.ncbi.nlm.nih.gov/39475292/
Children with HIV have a higher risk of developing tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb). This study utilized juvenile Mauritian cynomolgus macaques to investigate whether enhancing Vγ9+Vδ2+ γδ T cells with zoledronate treatment could improve TB resistance in HIV–TB coinfection. Researchers found that although boosting these immune cells temporarily increased their presence, it did not enhance the macaques’ ability to fight Mtb infection. These findings suggest that solely targeting γδ T cells may not be an effective strategy for improving TB immunity in immunocompromised individuals. These insights are crucial for developing better treatments for HIV–TB coinfections. Supported by ORIP (K01OD033539, P51OD011106) and NIAID.
The Buoyancy of Cryptococcal Cells and Its Implications for Transport and Persistence of Cryptococcus in Aqueous Environments
Jimenez et al., mSphere. 2024.
https://pubmed.ncbi.nlm.nih.gov/39601568/
Cryptococcosis is a major fungal pathogen that causes life-threatening infections. Researchers discovered that Cryptococcus has unique buoyancy properties that help with its survival and spread through water transport. This study explores how these fungal cells remain suspended in liquid, potentially enhancing their ability to survive in their surroundings and infect new hosts. Understanding the role of cellular buoyancy in Cryptococcus transport could improve strategies to prevent spread in aqueous settings, offering new insights into fungal infection risks. Supported by ORIP (T32OD011089), NIAID, and NHLBI.
Potent Broadly Neutralizing Antibodies Mediate Efficient Antibody-Dependent Phagocytosis of HIV-Infected Cells
Snow et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/39466835
This study investigates the role of potent broadly neutralizing antibodies (bNAbs) in mediating antibody-dependent cellular phagocytosis (ADCP) of HIV-infected cells. Researchers developed a novel cell-based approach to assess the ADCP of HIV-infected cells expressing natural conformations of the viral envelope glycoprotein, which allows the virus to infect a host cell. The findings in this study demonstrate that bNAbs facilitate efficient ADCP, highlighting their potential in controlling HIV infection by promoting immune clearance of infected cells. This study provides valuable insights into antibody-mediated immune mechanisms and supports the development of antibody-based therapies and vaccines targeting HIV. Supported by ORIP (P51OD011106) and NIAID.
Gene Editing of Pigs to Control Influenza A Virus Infections
Kwon et al., Emerging Microbes & Infections. 2024.
https://pubmed.ncbi.nlm.nih.gov/39083026/
A reduction in the efficacy of vaccines and antiviral drugs for combating infectious diseases in agricultural animals has been observed. Generating genetically modified livestock species to minimize susceptibility to infectious diseases is of interest as an alternative approach. The researchers developed a homozygous transmembrane serine protease 2 (TMPRSS2) knockout (KO) porcine model to investigate resistance to two influenza A virus (IAV) subtypes, H1N1 and H3N2. TMPRSS2 KO pigs demonstrated diminished nasal cavity viral shedding, lower viral burden, and reduced microscopic lung pathology compared with wild-type (WT) pigs. In vitro culturing of primary bronchial epithelial cells (PBECs) demonstrated delayed viral replication in TMPRSS2 KO pigs compared with WT pigs. This study demonstrates the potential use of genetically modified pigs to mitigate IAV infections in pigs and limit transmission to humans. Supported by ORIP (U42OD011140), NHLBI, NIAID, and NIGMS.
Cytomegalovirus Vaccine Vector-Induced Effector Memory CD4+ T cells Protect Cynomolgus Macaques From Lethal Aerosolized Heterologous Avian Influenza Challenge
Malouli et al., Nature Communications. 2024.
Development of a universal influenza vaccine that protects against seasonal strains and future pandemic influenza viruses is a necessity because of the limited efficacy of current influenza vaccines. Researchers developed a cynomolgus macaque β-herpesvirus cytomegalovirus (CyCMV) vaccine that targets the highly conserved proteins in influenza viruses. Male and female Mauritian-origin cynomolgus macaques (MCM) were vaccinated and boosted with the CyCMV vaccine prior to being challenged with small-particle aerosols containing highly pathogenic avian influenza (HPAI). MCMs receiving the CyCMV vaccine still presented with fever and pulmonary infiltration but demonstrated significant protection against HPAI-induced mortality. Unvaccinated MCMs challenged with HPAI did not survive. Survival was correlated with the magnitude of influenza-specific CD4+ T cells prior to infection. These results demonstrate the efficacy of a novel vaccine that protects against HPAI through a CD4 T cell–mediated response. Supported by ORIP (P51OD010425, P51OD011092) and NIAID.
Administration of Anti-HIV-1 Broadly Neutralizing Monoclonal Antibodies With Increased Affinity to Fcγ Receptors During Acute SHIV AD8-EO Infection
Dias et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-51848-y
Anti-HIV broadly neutralizing antibodies (bNAbs) mediate virus neutralization and antiviral effector functions through Fab and Fc domains, respectively. This study investigated the efficacy of wild-type (WT) bNAbs and modified bNAbs with enhanced affinity for Fcγ receptors (S239D/I332E/A330L [DEL]) after acute simian-HIVAD8-EO (SHIVAD8-EO) infection in male and female rhesus macaques. The emergence of the virus in the plasma and lymph nodes occurred earlier in macaques given DEL bNAbs than in those given WT bNAbs. Overall, the administration of DEL bNAbs revealed higher levels of immune responses. The results suggest that bNAbs with an enhanced Fcγ receptor affinity offer a potential therapeutic strategy by targeting HIV more effectively during early infection stages. Supported by ORIP (P40OD028116), NCI, and NIAID.