Selected Grantee Publications
- Clear All
- 37 results found
- Nonhuman Primate Models
- Vaccines/Therapeutics
- 2021
Cannabinoid Control of Gingival Immune Activation in Chronically SIV-Infected Rhesus Macaques Involves Modulation of the Indoleamine-2,3-Dioxygenase-1 Pathway and Salivary Microbiome
McDew-White et al., EBioMedicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34954656/
HIV-associated periodontal disease (PD) affects people living with HIV (PLWH) on combination anti-retroviral therapy (cART). Researchers used a systems biology approach to investigate the molecular, metabolome, and microbiome changes underlying PD and its modulation by phytocannabinoids (Δ9-THC) in rhesus macaques. Δ9-THC reduced IDO1 protein expression. The findings suggest that phytocannabinoids may help reduce gingival/systemic inflammation, salivary dysbiosis, and potentially metabolic disease in PLWH on cART. Supported by ORIP (P51OD011104, P51OD011133, U42OD010442), NIAID, NIDA, NIDDK, NIDCR, and NIMH.
The Pigtail Macaque (Macaca nemestrina) Model of COVID-19 Reproduces Diverse Clinical Outcomes and Reveals New and Complex Signatures of Disease
Melton et al., PLOS Pathogens. 2021.
https://pubmed.ncbi.nlm.nih.gov/34929014/
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.
AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset
Goertsen et al., Nature Neuroscience. 2021.
https://www.nature.com/articles/s41593-021-00969-4
Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system (CNS). This project focused on organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery. These results constitute an important step forward toward achieving the goal of engineered AAV vectors that can be used to broadly deliver gene therapies to the CNS in humans. Supported by ORIP (U24OD026638), NIMH, and NINDS.
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.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques
Sarkar et al., Frontiers in Immunology. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.757811/full
Researchers investigated the humoral response in vaccinated rhesus macaques with CD4+ T cell depletion, using the VC10014 DNA protein co-immunization vaccine platform (with gp160 plasmids and gp140 trimeric proteins derived from an HIV-1 infected subject). Both CD4+-depleted and non-depleted animals developed comparable Tier 1 and 2 heterologous HIV-1 neutralizing plasma antibody titers. Thus, primates generate HIV neutralizing antibodies in the absence of robust CD4+ T cell help, which has important implications for vaccine development. Supported by ORIP (P51OD011092, P40OD028116, U42OD023038, U42OD010426), NIAID, and NIDCR.
Prior Infection With SARS-CoV-2 WA1/2020 Partially Protects Rhesus Macaques Against Re-Infection With B.1.1.7 and B.1.351 Variants
Chandrashekar et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abj2641
Using the rhesus macaque model, researchers addressed whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against re-challenge with B.1.1.7 and B.1.351, known as the alpha and beta variants of concern, respectively. The investigators infected rhesus macaques with WA1/2020 and re-challenged them on day 35 with WA1/2020 or with the alpha or beta variants. Natural immunity to WA1/2020 led to robust protection against re-challenge with WA1/2020, partial protection against beta, and an intermediate degree of protection against alpha. These findings have important implications for vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern. Supported by ORIP (P51OD011106) and NCI.
A Large Repertoire of B Cell Lineages Targeting One Cluster of Epitopes in a Vaccinated Rhesus Macaque
Li et al., Vaccine. 2021.
https://www.sciencedirect.com/science/article/pii/S0264410X21010355?via%3Dihub=
A rhesus macaque that was serially immunized six times with the 8-mer epitope for human monoclonal antibody (mAb) 447-52D—specific to the V3 region of gp120 HIV-1—provided a rare opportunity to study the repertoire of antibodies produced upon vaccination against a particular antigenic site. From a blood sample taken 3 weeks after the last immunization, researchers produced 41 V3-specific recombinant mAbs by single B cell isolation and cloning. Sequence analysis revealed 21 B cell lineages (single and clonally related). The broad repertoire of Abs directed to a small antigenic site shows the targeting potency of a vaccine-elicited immune response in rhesus macaques. Supported by ORIP (P51OD011092, U42OD010246) and NIAID.
IL-21 Enhances Influenza Vaccine Responses in Aged Macaques with Suppressed SIV Infection
Kvistad et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.150888
Aging with HIV is associated with low-grade systemic inflammation, immune senescence, and impaired antibody (Ab) responses to such vaccines as influenza (flu). Researchers investigated the role of interleukin (IL)-21, a CD4 T follicular helper cell regulator, on flu vaccine Ab response in rhesus macaques in the context of age and controlled simian immunodeficiency virus (SIV) mac239 infection. They found that IL-21 enhanced flu vaccine-induced Ab responses in SIV+ (anti-retroviral therapy-suppressed) aged rhesus macaques, adjuvanting the flu vaccine by modulating lymph node germinal center activity. Thus, strategies to supplement IL-21 in aging might improve vaccine responses in people aging with HIV. Supported by ORIP (R24OD010947) and NIAID.
PD-1 Blockade and Vaccination Provide Therapeutic Benefit Against SIV by Inducing Broad and Functional CD8+ T Cells in Lymphoid Tissue
Rahman et al., Science Immunology. 2021.
https://doi.org/10.1126/sciimmunol.abh3034
Effective HIV therapies must induce functional CD8+ T cells and clear latent viral reservoirs during antiretroviral therapy (ART). Using a rhesus macaque model, researchers showed that therapeutic vaccination under ART using a CD40L plus TLR7 agonist-adjuvanted DNA/modified vaccinia Ankara vaccine regimen induced robust SIV-specific CD4+ and CD8+ T cell responses. Addition of an anti-PD-1 antibody to the SIV vaccine increased cytotoxic CD8+ T cells in lymph nodes after ART interruption, correlating to the control of virus and prolonged survival compared with the vaccine alone. Thus, combining immune checkpoint blockade with vaccination may be a promising avenue toward an HIV cure. Supported by ORIP (P51OD011132) and NIAID.