Selected Grantee Publications
- Clear All
- 30 results found
- Nonhuman Primate Models
- HIV/AIDS
- 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.
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.
Antiretroviral Therapy Timing Impacts Latent Tuberculosis Infection Reactivation in a Tuberculosis/Simian Immunodeficiency Virus Coinfection Model
Sharan et al., Journal of Clinical Investigation. 2021.
https://pubmed.ncbi.nlm.nih.gov/34855621/
In the rhesus macaque model for Mycobacterium tuberculosis plus simian immunodeficiency virus (SIV) co-infection, chronic immune activation rather than depletion of CD4+ T cells correlates with reactivation of latent tuberculosis infection (LTBI). Researchers administered combined antiretroviral therapy (cART) at 2 weeks post-SIV co-infection to study whether restoration of CD4+ T cell immunity occurred more broadly, and whether this prevented LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival led to better control of viral replication and reduced immune activation in the periphery and lung vasculature, thereby reducing the rate of SIV-induced reactivation. Supported by ORIP (K01OD031898, P51OD011133, P51OD011132, S10OD028653) and NIAID.
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.
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.
Circulating Integrin α4β7+ CD4 T Cells Are Enriched for Proliferative Transcriptional Programs in HIV Infection
Lakshmanappa et al., Federation of European Biochemical Societies Letters. 2021.
https://doi.org/10.1002/1873-3468.14163
HIV preferentially infects α4β7+ CD4 T cells, forming latent reservoirs that contribute to HIV persistence, yet the properties of α4β7+ CD4 T cells are poorly understood. Investigating HIV-infected humans and SHIV-infected rhesus macaques, investigators demonstrated that α4β7+ CD4 T cells in blood are enriched for genes regulating cell cycle progression and cellular metabolism. In contrast, rectal α4β7+ CD4 T cells exhibited a core tissue-residency gene expression program. These features were conserved across primate species, suggesting that the tissue environment influences memory T-cell transcriptional networks. These findings provide an important foundation for understanding the role of α4β7 in HIV infection. Supported by ORIP (K01OD023034, R24OD010976) 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.
Blocking α4β7 Integrin Delays Viral Rebound in SHIVSF162P3-Infected Macaques Treated with Anti-HIV Broadly Neutralizing Antibodies
Frank et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abf7201
To explore therapeutic potentials of combining anti-HIV broadly neutralizing antibodies (bNAbs) with α4β7 integrin blockade using the monoclonal antibody Rh-α4β7, investigators treated SHIVSF162P3-infected, viremic macaques with bNAbs only or bNAbs and Rh-α4β7. Treatment with bNAbs alone decreased viremia below 200 copies/ml in eight out of eight macaques, but seven of the monkeys rebounded within 3 weeks. In contrast, three of six macaques treated with both Rh-α4β7 and bNAbs maintained viremia below 200 copies/ml for 21 weeks, whereas three of those monkeys rebounded after 6 weeks. These findings suggest that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques. Supported by ORIP (P51OD011104, U42OD010568, U42OD024282, P40OD028116), NIAID, and NCI.
Interleukin-15 Response Signature Predicts RhCMV/SIV Vaccine Efficacy
Barrenäs et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009278
Standard immunogenicity measures do not predict efficacy of a vaccine based on strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV). This vaccine robustly protects just over half of immunized monkeys. Using functional genomics, researchers found that RhCMV/SIV efficacy is correlated with a vaccine-induced response to interleukin-15 (IL-15) that includes modulation of immune cell, inflammation, toll-like receptor signaling, and cell death programming pathways. RhCMV/SIV imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited CD8+ T cells to mediate protection against SIV. Supported by ORIP (P51OD010425, P51OD011092), NIAID, and NCI.