Selected Grantee Publications
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Engineered Deletions of HIV Replicate Conditionally to Reduce Disease in Nonhuman Primates
Pitchai et al., Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39116226/
Current antiretroviral therapy (ART) for HIV is limited by the necessity for continuous administration. Discontinuation of ART leads to viral rebound. A therapeutic interfering particle (TIP) was developed as a novel single-administration HIV therapy using defective interfering particles. TIP treatment in two humanized mouse models demonstrated a significant reduction in HIV viral load. TIP intervention was completed 24 hours prior to a highly pathogenic simian immunodeficiency virus (SIV) challenge in a nonhuman primate (NHP) rhesus macaque infant model. Compared to untreated SIV infection, NHPs that received TIP treatment displayed no visible signs of SIV-induced AIDS and exhibited improved seroconversion and a significant survival advantage to the 30-week clinical endpoint. Peripheral blood mononuclear cells isolated from HIV-infected patients showed that TIP treatment reduced HIV outgrowth. This study demonstrates the potential use of a single-administration TIP for HIV treatment. Supported by ORIP (P51OD011092, U42OD010426), NCI, NIAID, and NIDA.
Identifying Mitigating Strategies for Endothelial Cell Dysfunction and Hypertension in Response to VEGF Receptor Inhibitors
Camarda et al., Clinical Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39282930/
Vascular endothelial growth factor receptor inhibitor (VEGFRi) use can improve survival in patients with advanced solid tumors, but outcomes can worsen because of VEGFRi-induced hypertension, which can increase the risk of cardiovascular mortality. The underlying pathological mechanism is attributed to endothelial cell (EC) dysfunction. The researchers performed phosphoproteomic profiling on human ECs and identified α-adrenergic blockers, specifically doxazosin, as candidates to oppose the VEGFRi proteomic signature and inhibit EC dysfunction. In vitro testing of doxazosin with mouse, canine, and human aortic ECs demonstrated EC-protective effects. In a male C57BL/6J mouse model with VEGFRi-induced hypertension, it was demonstrated that doxazosin prevents EC dysfunction without decreasing blood pressure. In canine cancer patients, both doxazosin and lisinopril improve VEGFRi-induced hypertension. This study demonstrates the use of phosphoproteomic screening to identify EC-protective agents to mitigate cardio-oncology side effects. Supported by ORIP (K01OD028205), NCI, NHGRI, and NIGMS.
Bone Marrow Transplantation Increases Sulfatase Activity in Somatic Tissues in a Multiple Sulfatase Deficiency Mouse Model
Presa et al., Communications Medicine. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11502872/pdf/43856_2024_Article_648.pdf
Multiple Sulfatase Deficiency (MSD) is a rare genetic disorder where patients demonstrate loss of function mutations in the SUMF1 gene, resulting in a severe reduction in sulfatase activity. This enzyme deficiency causes impaired lysosomal function and widespread inflammation, leading to clinical manifestations like neurodegeneration, vision and hearing loss, and cardiac disease. The researchers evaluated the therapeutic potential of hematopoietic stem cell transplant (HSCT) to initiate cross-correction, where functional sulfatase enzymes secreted from the healthy donor cells are taken up to restore function in enzyme-deficient host cells. Bone marrow from healthy male and female B6-Sumf1(+/+) mice were transplanted into B6-Sumf1(S153P/S153P) mice, a model for MSD. The results showed that HSCT is suitable to rescue sulfatase activity in peripheral organs, such as the liver, spleen, and heart, but is not beneficial alone in inhibiting the central nervous system pathology of MSD. Supported by ORIP (U54OD020351, U54OD030187, U42OD010921) and NCI.
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.
Dual Blockade of IL-10 and PD-1 Leads to Control of SIV Viral Rebound Following Analytical Treatment Interruption
Pereira Ribeiro et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39266691
Pereira Ribeiro et al. tested a hypothesis that blockading two immune molecules, IL-10 and PD‑1, following treatment interruption could help control viral rebound in antiretroviral therapy (ART)–treated rhesus macaques infected with simian immunodeficiency virus (SIV), a nonhuman analogue of HIV. When measured at 24 weeks following treatment interruption, durable control of viral rebound was seen in 9 of 10 combo-treated macaques. The investigators also found that they could predict the control of viral rebound based on the induction of inflammatory cytokines, proliferation of effector CD8+ T cells, and reduced expression of BCL-2 in CD4+ T cells prior to treatment interruption. These results could provide a way to achieve long-lasting control of HIV infection after discontinuing ART. Supported by ORIP (U42OD011023, P51OD011132), NCI, and NIAID.
The Effect of Common Paralytic Agents Used for Fluorescence Imaging on Redox Tone and ATP Levels in Caenorhabditis elegans
Morton et al., PLOS One. 2024.
https://pubmed.ncbi.nlm.nih.gov/38669260
Caenorhabditis elegans is a highly valuable model organism in biological research. However, these worms must be paralyzed for most imaging applications, and the effect that common chemical anesthetics may have on the parameters measured—especially biochemical measurements such as cellular energetics and redox tone—is poorly understood. In this study, the authors used two reporters—QUEEN-2m for relative ATP levels and reduction-oxidation–sensitive green fluorescent protein for redox tone—to assess the impact of commonly used chemical paralytics. The results show that all chemical anesthetics at doses required for full paralysis alter redox tone and/or ATP levels, and anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. Therefore, it is important to tailor the use of anesthetics to different endpoints and experimental questions and to develop less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters. Supported by ORIP (P40OD010440, R44OD024963) and NIEHS.
Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Nelson et al., Science Immunology. 2024.
https://www.science.org/doi/10.1126/sciimmunol.adm7097
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env—SOSIP—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut. Supported by ORIP (P51OD011107), NCI, and NIAID.
Anti–PD-1 Chimeric Antigen Receptor T Cells Efficiently Target SIV-Infected CD4+ T Cells in Germinal Centers
Eichholtz et al., The Journal of Clinical Investigation. 2024.
https://pubmed.ncbi.nlm.nih.gov/38557496/
Researchers conducted adoptive transfer of anti–programmed cell death protein 1 (PD-1) chimeric antigen receptor (CAR) T cells in simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes on antiretroviral therapy (ART). In some macaques, anti–PD-1 CAR T cells expanded and persisted concomitant with the depletion of PD-1+ memory T cells—including lymph node CD4+ follicular helper T cells—associated with depletion of SIV RNA from the germinal center. Following CAR T infusion and ART interruption, SIV replication increased in extrafollicular portions of lymph nodes, plasma viremia was higher, and disease progression accelerated, indicating that anti–PD-1 CAR T cells depleted PD-1+ T cells and eradicated SIV from this immunological sanctuary. Supported by ORIP (U42OD011123, U42OD010426, P51OD010425, P51OD011092), NCI, NIAID, and NIDDK.
Early Antiretroviral Therapy in SIV-Infected Rhesus Macaques Reveals a Multiphasic, Saturable Dynamic Accumulation of the Rebound Competent Viral Reservoir
Keele et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38593120/
Researchers studied the dynamics of rebound-competent viral reservoir (RCVR) establishment in male and female rhesus macaques and assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of antiretroviral therapy (ART) after 1 year. All rhesus macaques rebounded between 7 and 16 days after ART, with 3 to 28 rebound lineages. Calculated reactivation rates per pre-ART plasma viral load were consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks after infection. The data highlight the heterogeneity of the RCVR between rhesus macaques, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection. Supported by ORIP (P51OD011092), NCI, and NIAID.