Selected Grantee Publications
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- 281 results found
- Aquatic Vertebrate Models
- Nonhuman Primate Models
Phagocytosis by an HIV Antibody Is Associated with Reduced Viremia Irrespective of Enhanced Complement Lysis
Spencer et al., Nature Communications. 2022.
https://doi.org/10.1038/s41467-022-28250-7
Researchers used the bNAb 10E8v4 targeting the HIV Env protein to examine the role of antibody-mediated effector and complement (C′) activity when 10E8v4 was administered prophylactically to rhesus monkeys challenged with simian-human immunodeficiency virus (SHIV). With sub-protective dosing, the researchers found a 78–88% reduction in post-acute viremia that was associated with 10E8v4–mediated phagocytosis. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to therapeutic efficacy against SHIV, while C′ functions do not contribute to efficacy in this context. This research informs the design of bNAb modifications for improving the protective efficacy of this therapeutic approach against HIV. Supported by ORIP (P51OD011092, U42OD023038) and NIAID.
Natural Disaster and Immunological Aging in a Nonhuman Primate
Watowich et al., PNAS. 2022.
https://www.pnas.org/content/119/8/e2121663119
Weather-related disasters can exacerbate existing morbidities and increase mortality risk. Researchers examined Hurricane Maria’s impact on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes and was correlated with age-associated alterations in gene expression, in addition to expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. These findings illuminate that natural disasters might become biologically embedded and contribute to earlier onset of disease and death. Supported by ORIP (P40OD012217), NIA, NIMH.
The Early Life Microbiota Mediates Maternal Effects on Offspring Growth in a Nonhuman Primate
Petrullo et al., iScience. 2022.
https://www.doi.org/10.1016/j.isci.2022.103948
Mammalian mothers influence offspring development by providing nutrients and other bioactive compounds through the placenta or milk. A relatively unexplored mechanism for maternal effects is vertical transmission of bacteria through milk to the infant gut. Infants that receive more glycan-utilizing bacteria from milk might better exploit oligosaccharides, which could improve nutrition and accelerate growth. Researchers found that first-time vervet mothers harbored a milk bacterial community that was less diverse due to the dominance of Bacteroides fragilis, a glycan-utilizing bacteria. These low-parity females had infants that grew faster, suggesting that vertical transmission of bacteria via milk can mediate maternal effects on growth. These results indicate non-nutritive milk constituents play important roles in development. Commercial milk formula might need to be improved or supplemented to better support infant health. Supported by ORIP (P40OD010965) and NCATS.
Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection
Curtis et al., mSphere. 2022.
https://www.doi.org/10.1128/msphere.00839-21
A tailored, effective HIV vaccine is needed to prevent mother-to-child viral transmission. In nonhuman primate models, infection with simian–human immunodeficiency virus (SHIV) can be prevented by administering broadly neutralizing HIV envelope (Env)–specific antibodies. Investigators tested the efficacy of an intramuscular vaccine regimen against SHIV infection in male and female infant rhesus macaques. The vaccine induced Env-specific antibodies in plasma, with antibody-dependent cellular cytotoxicity and phagocytic function. These antibodies, however, were insufficient for protection against infection. Future studies could focus on improving the breadth of antibody response and improving cell-mediated immunity. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
CAR/CXCR5–T Cell Immunotherapy Is Safe and Potentially Efficacious in Promoting Sustained Remission of SIV Infection
Pampusch et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1009831
HIV and simian immunodeficiency virus (SIV) replication are concentrated within the B cell follicles of secondary lymphoid tissues. In this study, the researchers developed immunotherapeutic chimeric antigen receptor (CAR) T cells that home to follicles and clear SIV-infected cells in a rhesus macaque model. The CAR T cells localized to the follicle, replicated, and interacted directly with infected cells. Most of the treated animals maintained lower viral loads in the blood and follicles, compared to control animals. These findings demonstrate the safety and potential efficacy of this immunotherapy approach for long-term remission of HIV without requiring the lifelong use of antiretroviral therapy. Supported by ORIP (P51OD011106), NIAID, and NHLBI.
Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques
Boby et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.835686
Recent studies suggest that people with HIV—particularly those not receiving antiretroviral therapy or those with low CD4 cell counts—are at increased risk of severe illness from SARS‑CoV-2 coinfection. Angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, is likely to play an important role in modulating physiological and pathological events during HIV infection. In this study, the researchers used a rhesus macaque model to characterize the expression profiles of ACE2, other renin-angiotensin system (RAS)–associated genes (AGTR1/2, ADAM17, and TMPRSS2), and inflammatory cytokines (IL-1β, IL-6, and TNF‑α) in the jejunum and lung during simian immunodeficiency virus (SIV) infection. SIV infection was associated with multiple changes in gene expression, including downregulation of ACE2, which could lead to loss of gut homeostasis. Further studies could provide insight on the role of RAS-associated proteins during HIV and SARS-CoV-2 co-infection. Supported by ORIP (P51OD011104) and NIDDK.
Functional and Ultrastructural Analysis of Reafferent Mechanosensation in Larval Zebrafish
Odstrcil et al., Current Biology. 2022.
https://www.sciencedirect.com/science/article/pii/S096098222101530X
All animals need to differentiate between exafferent stimuli (caused by the environment) and reafferent stimuli (caused by their own movement). Researchers characterized how hair cells in zebrafish larvae discriminate between reafferent and exafferent signals. Dye labeling of the lateral line nerve and functional imaging was combined with ultra-structural electron microscopy circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies, and dopaminergic signals from the hypothalamus may affect threshold modulation. Findings suggest that this circuit is the core implementation of mechanosensory reafferent suppression in these young animals. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Heritability of Social Behavioral Phenotypes and Preliminary Associations with Autism Spectrum Disorder Risk Genes in Rhesus Macaques: A Whole Exome Sequencing Study
Gunter et al., Autism Research. 2022.
https://onlinelibrary.wiley.com/doi/full/10.1002/aur.2675
Investigators quantified individual variation in social interactions among juvenile rhesus macaques of both sexes using both a standard macaque ethogram (a catalogue of animal behavior over time) and a macaque-relevant modification of the human Social Responsiveness Scale to study genetic influences on key aspects of social behavior and interactions. The analyses demonstrate that various aspects of juvenile social behavior exhibit significant genetic heritability, with quantitative genetic effects similar to autism spectrum disorder (ASD) in human children. The significant genetic and sequencing data may be used to examine potential genetic associations with human ASD. Supported by ORIP (P51OD011132), NHGRI and NIMH.
Expression, Activity, and Regulation of Phosphorylating Enzymes in Tissues and Cells Relevant to HIV-1 Sexual Transmission
Hu et al., AIDS Research and Human Retroviruses. 2022.
https://www.doi.org/10.1089/AID.2020.0250
Phosphorylating enzymes (PEs) are critical for activating nucleoside/nucleotide reverse transcriptase inhibitors (e.g., tenofovir [TFV]), but limited information is available about the expression of PEs in the female genital tract and colon tissue. Investigators compared the mRNA expression of seven PEs involved in metabolism of TFV in cervicovaginal and colon tissues. This work involved human, pigtailed macaque, and rabbit tissues; human cervicovaginal epithelial cell lines; T cell lines; and primary CD4+ T cells. Taken together, this study suggests that TFV activation differs among immune cells and local tissues under varying conditions. Additionally, the variability of PE expression levels found across species provides critical information to assist with the interpretation of data obtained using these animal models. Supported by ORIP (P51OD010425) and NIAID.
Estimation of the In Vivo Neutralization Potency of eCD4Ig and Conditions for AAV-Mediated Production for SHIV Long-Term Remission
Goyal et al., Science Advances. 2022.
https://www.doi.org/10.1126/sciadv.abj5666
The engineered protein eCD4Ig, a synthetic antibody-like inhibitor designed to limit HIV entry into cells, shows promise as an approach to achieve HIV remission without antiretroviral therapy. Researchers used mathematical modeling to characterize in vivo antiviral neutralization of eCD4Ig, as well as possible antibody-dependent cell-mediated cytotoxicity effects, in rhesus macaques infected with simian–human immunodeficiency virus (SHIV) (sex not specified). The research team modeled SHIV and pharmacokinetics dynamics and projected the levels of eCD4Ig needed with a viral vector production approach to suppress SHIV viremia. The data suggest that endogenous, continuous expression of eCD4Ig could overcome the diminishing effects of antidrug antibodies and allow long-term remission of SHIV viremia in nonhuman primates. Supported by ORIP (P51OD011132) and NIAID.