Selected Grantee Publications
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- 59 results found
- HIV/AIDS
- Women's Health
- 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.
Integrative Multi-omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes in Ovarian Cancer
Rosario et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39638782
Recurrent ovarian cancer (OC) is the deadliest gynecological malignancy, with a 5-year survival rate of 50% and a median progression-free survival (PFS) of 1.9 to 2.1 months. A trial cohort of 40 patients was treated with a combination of the anti-PD-1 pembrolizumab, the anti–vascular endothelial growth factor bevacizumab, and cyclophosphamide. The investigators conducted a multi-omics analysis—including transcriptomic analysis, digital spatial profiling, 16s-rRNA sequencing, and metabolomics—to understand the underlying mechanisms for the enhanced PFS to a median of 10.2 months and overall response rate of 47.5%. Multi-omics analysis highlighted the formation of tertiary lymphoid structures known to improve responses to immunotherapy, differential microbial patterns, and alterations in the metabolites in three key metabolism pathways that enhanced immune response in patients to produce a durable clinical response. These findings highlight the importance of the tumor microenvironment and the gut microbiome, along with its metabolites, in elevating the efficacy of the cocktail therapy in recurrent OC patients, thereby enhancing their survival and quality of life. Supported by ORIP (S10OD024973) and NCI.
A Switch from Glial to Neuronal Gene Expression Alterations in the Spinal Cord of SIV-Infected Macaques on Antiretroviral Therapy
Mulka et al., Journal of Neuroimmune Pharmacology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38862787/
Up to one-third of patients with HIV experience HIV-associated peripheral neuropathy, affecting sensory pathways in the spinal cord. Spinal cord sampling is limited in people with HIV. Researchers examined gene expression alterations in the spinal cords of simian immunodeficiency virus (SIV)-infected male pigtail macaques with and without antiretroviral therapy (ART), using RNA sequencing at key time points throughout infection. Results indicate a shift from glial cell-associated pathways to neuronal pathways in SIV-infected animals receiving ART. These findings suggest that neurons, rather than glia, are predominantly involved in ART-related neurotoxicity and offer new insights into therapeutic strategies for maintaining synaptic homeostasis. Supported by ORIP (U42OD013117, T32OD011089) and NINDS.
Potent Broadly Neutralizing Antibodies Mediate Efficient Antibody-Dependent Phagocytosis of HIV-Infected Cells
Snow et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/39466835
This study investigates the role of potent broadly neutralizing antibodies (bNAbs) in mediating antibody-dependent cellular phagocytosis (ADCP) of HIV-infected cells. Researchers developed a novel cell-based approach to assess the ADCP of HIV-infected cells expressing natural conformations of the viral envelope glycoprotein, which allows the virus to infect a host cell. The findings in this study demonstrate that bNAbs facilitate efficient ADCP, highlighting their potential in controlling HIV infection by promoting immune clearance of infected cells. This study provides valuable insights into antibody-mediated immune mechanisms and supports the development of antibody-based therapies and vaccines targeting HIV. Supported by ORIP (P51OD011106) and NIAID.
Phenotypic Characterization of Subtype A and Recombinant AC Transmitted/Founder Viruses From a Rwandan HIV-1 Heterosexual Transmission Cohort
Yue et al., Viruses. 2024.
https://pubmed.ncbi.nlm.nih.gov/39599821
HIV-1 is classified into several phylogenetic groups and subgroups, and to be effective, a vaccine would require broad activity across diverse viral strains. The most widespread group, M, is subdivided into several subgroups (A–D, F–H, J, K, and L). In a previous study, these researchers analyzed cohorts of people with recent or acute HIV infection in Rwanda. Subtype A was the dominant subtype, but a significant number of infections were caused by recombinants of subtypes A and C. This study assessed the characteristics of 16 infectious molecular clones (IMCs) of subtype A or AC recombinant viruses. Viral replication scores varied among the IMCs, and amino acid substitutions in the viral Gag gene were linked to higher replication activity. The sensitivity of different clones to broadly neutralizing antibodies also was assessed. This panel of well-characterized viral IMCs will support studies required to develop an effective HIV-1 vaccine. Supported by ORIP (P51OD011132) and NIAID.
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.
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.
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.