Selected Grantee Publications
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.
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.
SARS-CoV-2 Vaccines Elicit Durable Immune Responses in Infant Rhesus Macaques
Garrido et al., Science Immunology. 2021.
https://immunology.sciencemag.org/content/6/60/eabj3684
The immunogenicity of two SARS-CoV-2 vaccines was evaluated in both sexes of infant rhesus macaques (n=8/group). Neither vaccine, stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion, induced adverse effects. Both elicited high magnitude neutralizing antibody titers peaking at week 6. S-specific T cell responses were dominated by IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. These data provide proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity to decrease transmission of COVID-19. Supported by ORIP (P51OD011107), NIAID, and NCI.
IL-21 and IFNα Therapy Rescues Terminally Differentiated NK Cells and Limits SIV Reservoir in ART-Treated Macaques
Harper et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23189-7
Nonpathogenic simian immunodeficiency virus (SIV) infections in natural hosts, such as vervet monkeys, are characterized by a lack of gut microbial translocation, robust secondary lymphoid natural killer cell responses, and limited SIV dissemination in lymph node B-cell follicles. Using antiretroviral therapy-treated, SIV-infected rhesus monkeys—a pathogenic model—researchers showed that interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. The correlated reduction of replication-competent SIV in lymph node demonstrates that vervet-like natural killer cell differentiation can be rescued in rhesus monkeys to promote viral clearance. Supported by ORIP (P51OD011132, R24OD010947), NIAID, and NCI.
Tract Pathogen-Mediated Inflammation Through Development of Multimodal Treatment Regimen and Its Impact on SIV Acquisition in Rhesus Macaques
Bochart et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009565
In addition to being premier HIV models, rhesus macaques are models for other infectious diseases and colitis, where background colon health and inflammation may confound results. Starting with the standard specific-pathogen-free (SPF) model, researchers established a gastrointestinal pathogen-free (GPF) colony via multimodal therapy (enrofloxacin, azithromycin, fenbendazole, and paromomycin) to eliminate common endemic pathogens (EPs). This treatment combined with continued pathogen exclusion eliminated common EPs, improved mucosal barriers, and reduced mucosal and systemic inflammation without microbiota disruption. GPF animals challenged with SIV intrarectally demonstrated a more controlled and consistent rate of SIV acquisition, suggesting the value of this model for HIV studies. Supported by ORIP (U42OD023038, P51OD011092), NCI, and NIAID.
Postpubertal Spermatogonial Stem Cell Transplantation Restores Functional Sperm Production in Rhesus Monkeys Irradiated Before and After Puberty
Shetty et al., Andrology. 2021.
https://onlinelibrary.wiley.com/doi/10.1111/andr.13033
Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). Prepubertal rhesus monkeys (n=6) were unilaterally castrated, and the remaining testes irradiated twice to insure loss of SSCs; the animals were treated with a vehicle or GnRH antagonist for 8 weeks (n=3/treatment). The cryopreserved prepubertal testicular tissue was allergenically transplanted into the intact testes of the monkeys after puberty. Recovery of viable donor epididymal sperm was observed in half the monkeys. These results illustrate that sperm production can be restored in primates by transplantation of testicular cells from cryopreserved untreated prepubertal testes into seminiferous tubules of the remaining testes. Supported by ORIP (P51OD011092), NICHD, and NCI.
Modulation of MHC-E Transport by Viral Decoy Ligands Is Required for RhCMV/SIV Vaccine Efficacy
Verweij et al., Science. 2021.
https://doi.org/10.1126/science.abe9233
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (SIV) vaccines elicit strong CD8+ T cell responses that can clear SIV infections. Peptides targeted by these T cells are presented on major histocompatibility complex (MHC) II and MHC-E rather than MHC-Ia. Researchers showed that VL9 drives intracellular transport of MHC-E and recognition of RhCMV-infected targets by MHC-E-restricted CD8+ T cells. Specific-pathogen-free (SPF) rhesus macaques vaccinated with a mutant 68-1 RhCMV lacking VL9 showed no priming of MHC-E-restricted CD8+ T cells and no protection against SIV, suggesting that future effective CMV-based HIV vaccines will require MHC-E-restricted CD8+ T cell priming. Supported by ORIP (U42OD023038, P51OD011092), NIAID, and NCI.
Functional Convergence of a Germline-Encoded Neutralizing Antibody Response in Rhesus Macaques Immunized with HCV Envelope Glycoproteins
Chen et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.013
Immunoglobulin heavy chain variable gene IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection in humans. An IGHV1-69 ortholog, VH1.36, is preferentially used for bnAbs isolated from rhesus macaques immunized against HCV Env. Researchers investigated the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by HCV Env vaccination of macaques and compared their findings to IGHV1-69-encoded bnAbs from HCV patients. The investigators found that macaque VH1.36- and human IGHV1-69-encoded bnAbs share many common features, which provides an excellent framework for rational HCV vaccine design and testing. Supported by ORIP (P51OD011133, U42OD010442), NIAID, NCI, and NIGMS.
Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
Gramatica et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.02393-20
Activation of latent HIV-1 expression could benefit many HIV cure strategies. Researchers evaluated two AKT/mTOR activators, SB-216763 and tideglusib, as a potential new class of LRAs. The drugs reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy without causing T cell activation or impaired effector function of cytotoxic T lymphocytes or NK cells. When tested in vivo in monkeys, tideglusib showed unfavorable pharmacodynamic properties and did not reverse SIV latency. The discordance between the ex vivo and in vivo results underscores the importance of developing novel LRAs that allow systemic drug delivery to relevant anatomical compartments. Supported by ORIP (P51OD011092), NIAID, NIGMS, NIMH, and NCI.