Selected Grantee Publications
Dynamics and Origin of Rebound Viremia in SHIV-Infected Infant Macaques Following Interruption of Long-Term ART
Obregon-Perko et al., JCI Insight. 2021.
https://pubmed.ncbi.nlm.nih.gov/34699383/
Animal models that recapitulate human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics, mechanisms of disease, and testing of vaccines and therapeutics. A group of male pigtail macaques (PTMs) were euthanized either 6- or 21-days after SARS-CoV-2 viral challenge and demonstrated mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, virus-targeting T cells were predominantly CD4+, increases in circulating inflammatory and coagulation markers, pulmonary pathologic lesions, and the development of neutralizing antibodies were observed. Collectively, the data suggests PTMs are a valuable model to study COVID-19 pathogenesis and may be useful for testing vaccines and therapeutics. Supported by ORIP (P51OD011104) and NIAID.
Tissue-Specific Transcriptional Profiling of Plasmacytoid Dendritic Cells Reveals a Hyperactivated State in Chronic SIV Infection
Lee et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009674
Persistent immune activation is an obstacle to optimal health for people living with HIV. Using RNA sequencing, researchers investigated the immunostimulatory potential of plasmacytoid dendritic cells (pDCs) in chronic SIV infection in rhesus macaques. They observed that pDCs have highly activated profiles in these animals. In contrast, pDCs from SIV-infected sooty mangabeys (natural hosts for SIV) had expression profiles similar to uninfected animals. In chronically infected rhesus macaques, interferon alpha transcripts were readily detected in lymph node-homing pDCs, but not those from blood. Therefore, pDCs are a major producer of type-I interferon in chronic SIV infection and could be a useful immunotherapy target. Supported by ORIP (R24OD010445, P51OD011132, P51OD011092, S10OD026799) and NIAID.
Gut Germinal Center Regeneration and Enhanced Antiviral Immunity by Mesenchymal Stem/Stromal Cells
Weber et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.149033
Researchers investigated the effects of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression in SIV-infected rhesus macaques. MSC treatment heightened virus-specific responses and reduced viral load. Clearance of SIV-positive cells from gut mucosal effector sites was correlated with regeneration of germinal centers, restoration of follicular B cells and T follicular helper cells, and enhanced antigen presentation by viral trapping within the follicular dendritic cell network. These changes were associated with enhanced gene expression for type I/II interferon signaling, B cell proliferation, and interleukin 7. MSC treatment also activated metabolic pathways associated with enhanced immunity and viral reduction. Supported by ORIP (P51OD011107) and NIAID.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.
Neutralizing Antibody Vaccine for Pandemic and Pre-Emergent Coronaviruses
Saunders et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03594-0
SARS-CoV-2 is a new member of the betacoronavirus (beta-CoV) genus, which also includes two common mild beta-CoVs and the life-threatening SARS-CoV-1 and MERS-CoV. Vaccines that elicit protective immunity against SARS-CoV-2 and beta-CoVs that circulate in animals could prevent future pandemics. Researchers designed a novel 24-mer SARS-CoV-2 receptor binding domain-sortase A conjugated nanoparticle vaccine (RBD-scNP). Investigators demonstrated that the immunization of macaques with RBD-scNP, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV, and multiple SARS-CoV-2 variants of concern. This pioneering approach serves as a multimeric protein platform for the further development of generalized anti-beta-CoV vaccines. Supported by ORIP (U42OD021458), NIAID, and NCI.