Selected Grantee Publications
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- Immunology
- Genetics
Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype
Gross et al., Nature Communications. 2025.
https://www.nature.com/articles/s41467-025-57632-w
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease in which immune cells infiltrate the central nervous system and promote deterioration of myelin and neurodegeneration. The capacity to regenerate myelin in the central nervous system diminishes with age. In this study, researchers used 2- to 3-month-old (young), 12-month-old (middle-aged), and 18- to 22-month-old (aged) C57BL/6 male and female mice. Results showed an upregulation of the senescence marker P16ink4a (P16) in microglial and macrophage cells within demyelinated lesions. Notably, treatment of senescent cells using genetic and pharmacological senolytic methods leads to enhanced remyelination in young and middle-aged mice but fails to improve remyelination in aged mice. These results suggest that therapeutic targeting of senescence-associated secretory phenotype components may improve remyelination in aging and MS. Supported by ORIP (R24OD036199), NIA, NINDS, and NIMH.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons et al., c. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674359/
Current HIV treatment strategies are focused on forced proviral reactivation and elimination of reactivated cells with immunological or toxin-based technologies. Researchers have proposed the use of a novel “block-lock-stop” approach, which entails the long-term durable silencing of viral expression and permanent transcriptional deactivation of the latent provirus. In the present study, the authors present this approach and its rationale. More research is needed to understand the (1) epigenetic architecture of integrated provirus, (2) cell types and epigenetic cell states that favor viral rebound, (3) molecular functions of Tat (a protein that controls transcription of HIV) and host factors that prevent permanent silencing, (4) human endogenous retrovirus silencing in the genome, and (5) approaches to generate defective proviruses. Additionally, community engagement is crucial for this effort. Supported by ORIP (K01OD031900), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS.
Antiretroviral Therapy Ameliorates Simian Immunodeficiency Virus–Associated Myocardial Inflammation by Dampening Interferon Signaling and Pathogen Response in the Heart
Robinson et al., The Journal of Infectious Diseases. 2023.
https://doi.org/10.1093/infdis/jiad105
HIV is associated with increased risk of cardiovascular disease, but the underlying mechanisms are not fully understood. Using RNA sequencing, investigators characterized the effects of simian immunodeficiency virus (SIV) infection on the hearts of male rhesus macaques. They demonstrated that SIV infection drives a canonical antiviral response in the heart, as well as dysregulation of genes involved in fatty acid shuttling and metabolism. Their findings suggest that antiretroviral therapy helps mitigate immune activation during viremic conditions and plays a cardioprotective role. Future studies are needed to assess the long-term effects of these dynamics. Supported by ORIP (P51OD011104), NIAID, NIMH, and NINDS.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
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.
A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies
McCann et al., Journal of Experimental Medicine. 2021.
https://doi.org/10.1084/jem.20201908
HIV-specific CD8+ T cells partially control viral replication but rarely provide lasting protection due to immune escape. Investigators showed that engrafting NSG mice with memory CD4+ T cells from HIV+ donors enables evaluation of autologous T cell responses while avoiding graft-versus-host disease. Treating HIV-infected mice with clinically relevant T cell products reduced viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an Interleukin-15 superagonist but was ultimately limited by the pervasive selection of escape mutations, recapitulating human patterns. This “participant-derived xenograft” model provides a powerful tool for developing T cell-based therapies for HIV. Supported by ORIP (R01OD011095), NIAID, NIDA, NIMH, NINDS, and NCATS.