Selected Grantee Publications
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- Infectious Diseases
- P40
- Genetics
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.
Comparison of the Immunogenicity of mRNA-Encoded and Protein HIV-1 Env-ferritin Nanoparticle Designs
Mu et al., Journal of Virology. 2024.
https://journals.asm.org/doi/10.1128/jvi.00137-24
Inducing broadly neutralizing antibodies (bNAbs) against HIV-1 remains a challenge because of immune system limitations. This study compared the immunogenicity of mRNA-encoded membrane-bound envelope (Env) gp160 to HIV-1 Env-ferritin nanoparticle (NP) technology in inducing anti-HIV-1 bNAbs. Membrane-bound mRNA encoding gp160 was more immunogenic than the Env-ferritin NP design in DH270 UCA KI mice, but at lower doses. These results suggest further analysis of mRNA design expression and low-dose immunogenicity studies are necessary for anti-HIV-1 bNAbs. Supported by ORIP (P40OD012217, U42OD021458) and NIAID.
Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates
Burdo et al., Gene Therapy. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11090835/
Nonhuman primates have served as a valuable resource for evaluating novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed. Together, these findings support the continued development of HIV eradicative cure strategies using CRISPR technology in humans. Supported by ORIP (P40OD012217, U42OD021458).
Early Detection of Pseudocapillaria tomentosa by qPCR in Four Lines of Zebrafish, Danio rerio (Hamilton 1882)
Schuster et al., Journal of Fish Diseases. 2023.
https://onlinelibrary.wiley.com/doi/10.1111/jfd.13773
The intestinal nematode Pseudocapillaria tomentosa in zebrafish (Danio rerio) causes profound intestinal lesions, emaciation, and death and is a promoter of a common intestinal cancer in zebrafish. This nematode has been detected in an estimated 15% of zebrafish laboratories. Adult worms are readily detected about 3 weeks after exposure by either histology or wet mount preparations of the intestine, and larval worms are inconsistently observed in fish before this time. A quantitative PCR (qPCR) test was recently developed to detect the worm in fish and water, and here the authors determined that the test on zebrafish intestines was effective for earlier detection. Supported by ORIP (R24OD010998, P40OD011021).
A Live Dengue Virus Vaccine Carrying a Chimeric Envelope Glycoprotein Elicits Dual DENV2–DENV4 Serotype-Specific Immunity
Young et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/36914616/
Dengue vaccine development is challenging because some virus-specific antibodies are protective, whereas others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to induce balanced protective immunity. To simplify live-virus vaccine design, investigators identified co-evolutionary constraints inherent in flavivirus virion assembly. They found that the chimeric virus replicated efficiently in vitro and in vivo and that a single inoculation induced type-specific neutralizing antibodies in male macaques. These findings can be applied to the development of bivalent live dengue vaccines that induce independent immunity to multiple serotypes. Supported by ORIP (P40OD012217) and NIAID.
Antibody-Based CCR5 Blockade Protects Macaques From Mucosal SHIV Transmission
Chang et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23697-6
The efficacy of antiretroviral therapy (ART) as pre-exposure prophylaxis against HIV is hindered by incomplete patient adherence and ART-resistant variants. Researchers found that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges with a CCR5-tropic simian-human immunodeficiency virus (SHIVSF162P3). Biweekly injection of Leronlimab at 50 mg/kg provided complete protection from SHIV infection. Tissue biopsies from protected macaques post-challenge revealed complete CCR5 receptor occupancy and an absence of viral DNA. After Leronlimab washout, transfer of hematologic cells into naïve monkeys did not transmit infection, supporting the initiation of clinical trials. Supported by ORIP (P51OD011092, K01OD026561, P40OD028116) and NIAID.
Epidemiological and Molecular Characterization of a Novel Adenovirus of Squirrel Monkeys After Fatal Infection During Immunosuppression
Rogers et al., Microbial Genomics. 2020.
https://pubmed.ncbi.nlm.nih.gov/32614763/
Adenoviruses frequently cause upper respiratory tract infections, often causing disseminated disease in immunosuppressed patients. A novel adenovirus was identified, squirrel monkey adenovirus 1 (SqMAdV-1), as the cause of a fatal infection in an immunocompromised squirrel monkey (Saimiri boliviensis). A nucleotide polymorphism at the stop codon of the DNA polymerase gene results in a 126 amino acid extension at the carboxy terminus. A single adenovirus variant, SqMAdV-3, has similarity to tufted capuchin (Sapajus apella) adenoviruses. The largest group of adenovirus variants detected, SqMAdV-2.0-2.16, has high similarity (93-99%) to the TMAdV, suggesting that squirrel monkeys may be the natural host of the TMAdV. Supported by ORIP (P40OD010938, R24OD018553), and NIAID.