Selected Grantee Publications
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- Vaccines/Therapeutics
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
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.
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.
Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, and Neuroinflammation
Chung et al., Cell Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37084732/
Very-long-chain fatty acids (VLCFAs) are the most abundant fatty acids in myelin. During age‑associated degeneration of myelin, glia are exposed to increased levels of VLCFAs. Investigators previously described a novel phenotype in patients that harbors a novel variant in the peroxisomal enzyme ACOX1. Here, they report that that glial loss of ACOX1 leads to an increase of VLCFAs, which results in a concomitant increase in sphingosine-1-phosphate (S1P). They found that suppressing S1P function attenuates the pathological phenotypes caused by excess VLCFAs. This work suggests that lowering of VLCFAs and S1P could be applied as a treatment avenue for multiple sclerosis. Supported by ORIP (R24OD022005, R24OD031447, P40OD018537), NINDS, and NICHD
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Sequential Intrahost Evolution and Onward Transmission of SARS-CoV-2 Variants
Gonzalez-Reiche et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239218/
Most patients with COVID-19 clear the virus upon resolution of acute infection, but a subset of immunocompromised individuals develop persistent SARS-CoV-2 infections. In this study, investigators describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of the Omicron BA.1 variant Omicron BA.1.23. The study demonstrated that in the presence of suboptimal immune responses, persistent viral replication is an important driver of SARS-CoV-2 diversification. This and other studies also highlight that strategies to prevent virus persistence and shedding and more effective therapies are needed to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. Supported by ORIP (S10OD026880, S10OD030463), NIAID, and NCATS.
Late Gene Expression–Deficient Cytomegalovirus Vectors Elicit Conventional T Cells That Do Not Protect Against SIV
Hansen et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070102/
Cytomegalovirus (CMV)–based vaccines aim to exploit unique immunological adaptations, including host manipulation and immune evasion strategies. Translating CMV-based vaccines from rhesus macaques to humans requires translating the immune factors responsible for efficacy, as well as vaccine vectors that are sufficiently safe for widespread use. Researchers examined the impact of a stringent attenuation strategy on vector-induced immune protection against simian immunodeficiency virus (SIV) in rhesus macaques of both sexes. They reported that elicited CD8+ T cells exclusively failed to protect against SIV challenge. These data suggest that late viral gene expression and/or residual in vivo spreading are required to induce protective CD8+ T cell responses. Supported by ORIP (P51OD011092, P51OD011107, S10OD016261), NCI, NIAID, and NCATS.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy Against HIV-1: A Phase 1 Clinical Trial
Julg et al., Nature Medicine. 2022.
https://www.doi.org/10.1038/s41591-022-01815-1
Previous evidence suggests that at least three broadly neutralizing antibodies (bNAbs) targeting different epitope regions are needed for robust treatment and control of HIV. The investigators evaluated the safety, tolerability, and pharmacokinetics of PGDM1400, an HIV-1 V2-glycan–specific antibody, in a first-in-human trial. The primary endpoints were safety, tolerability, pharmacokinetics, and antiviral activity. The trial met the prespecified endpoints in male and female adults. These data will help advance understanding of the capabilities, limitations, and future role of bNAb combinations in HIV prevention and care. Supported by ORIP (R01OD024917), NIAID, and NCATS.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.