Selected Grantee Publications
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- 266 results found
- Cardiovascular
- Infectious Diseases
Persistence of a Skewed Repertoire of NK Cells in People With HIV-1 on Long-Term Antiretroviral Therapy
Anderko et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551350
HIV-1 infection alters the natural killer (NK) cell phenotypic and functional repertoire. A rare population of FcRγ−NK cells exhibiting characteristics of traditional immunologic memory expands in people with HIV. In a longitudinal analysis during the first 4 years of antiretroviral therapy (ART), a skewed repertoire of cytokine unresponsive FcRγ−memory-like NK cells persisted in people with HIV, and surface expression of CD57 and KLRG1 increased, suggesting progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing antibody titers to human cytomegalovirus (CMV), with human CMV viremia detected in approximately one-third of people studied during the first 4 years of ART. About 40% of people studied displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis. These findings indicate that NK cell irregularities persist in people with HIV despite long-term ART. Supported by ORIP (P51OD011132, S10OD026799), NIAID, and NHLBI.
Surgical Protocol for Partial Heart Transplantation in Growing Piglets
Medina, World Journal for Pediatric and Congenital Heart Surgery. 2024.
https://pubmed.ncbi.nlm.nih.gov/38780414/
Researchers are interested in using partial heart transplantation (i.e., only the part of the heart containing the necessary heart valve is transplanted) to deliver growing heart valve implants. This novel technique allows partial heart transplants to grow, similar to the valves in heart transplants. More work is needed, however, to understand the underlying biological mechanisms of this approach and achieve progress in clinical care. In the present study, the authors present a surgical protocol for partial heart transplantation in growing piglets. This model will enable other researchers to seek fundamental knowledge about the nature of partial heart transplants. Supported by ORIP (U42OD011140) and NHLBI.
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
SIV Infection Is Associated With Transient Acute-Phase Steatosis in Hepatocytes In Vivo
Derby, Viruses. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10892327/
Metabolic dysfunction–associated fatty liver disease (MAFLD) in people with HIV has become an increasing concern, but little is known about liver-specific changes underlying HIV-related MAFLD. Using rhesus macaques (sex not specified), researchers examined the timing of pathogenic changes within the liver during simian immunodeficiency virus (SIV) infection. Their findings suggest differential pathologies associated with the acute and chronic phases of infection. This work highlights the early damage inflicted on the liver by SIV/HIV infection and indicates that damage to the hepatocytes plays a specific role. Overall, the authors conclude that therapeutic interventions targeting metabolic function may benefit liver health in people who have recently received an HIV diagnosis. Supported by ORIP (P51OD011107, P51OD011092) and NIAID.
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
Potent Antibody-Dependent Cellular Cytotoxicity of a V2-Specific Antibody Is Not Sufficient for Protection of Macaques Against SIV Challenge
Grunst et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38252675/
Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with decreased risk of HIV acquisition. Researchers tested the ability of PGT145, an antibody that neutralizes genetically diverse HIV-1 isolates, to protect rhesus macaques against simian immunodeficiency virus (SIV) via ADCC activity. They found that a single amino acid substitution in the V2 core epitope of the SIV envelope increases PGT145 binding and confers sensitivity to neutralization. Peak and chronic phase viral loads were lower, and time to peak viremia was delayed. They concluded that ADCC is insufficient for protection by this antibody, but increasing the affinity of antibody binding could confer partial protection. Supported by ORIP (P51OD011106), NIAID, and NCI.
SHIV-C109p5 NHP Induces Rapid Disease Progression in Elderly Macaques with Extensive GI Viral Replication
Bose et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38299866/
Researchers are interested in developing animal models infected with simian–human immunodeficiency virus (SHIV) to better understand prevention of HIV acquisition. Researchers generated pathogenic SHIV clade C transmitted/founder stock by in vivo passage using geriatric rhesus macaques of both sexes. They reported that the infection resulted in high sustained viral loads and induced rapid pathology and wasting, necessitating euthanasia between 3 and 12 weeks post-infection. The extensive viral replication in gut and lymphoid tissues indicated a fit viral stock. This work provides a new nonhuman primate model for HIV pathogenicity and cure studies. Supported by ORIP (R24OD010947) and NIDDK.
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.