Selected Grantee Publications
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- Immunology
- P51
Long-Term Evolutionary Adaptation of SIVcpz toward HIV-1 Using a Humanized Mouse Model
Schmitt et al., Journal of Medical Primatology. 2022.
https://www.doi.org/10.1111/jmp.12616
Chimpanzee-derived simian immunodeficiency viruses (SIVcpz) are thought to have evolved into the highly pathogenic HIV-1 Group M, but the genetic adaptations required for SIV progenitor viruses to become pathogenic and established as HIVs in the human population have remained unclear. Using humanized mice of both sexes, researchers mimicked the evolution of SIVcpz into HIV-1 Group M through serial passaging. After four generations, the researchers observed increased initial viral load, increased CD4+ T cell decline, and nonsynonymous substitutions. Overall, these data indicate increased viral fitness and pathogenicity. This work also demonstrates the utility of humanized mice in recreating the adaptive pressures necessary for the evolution of SIVcpz into HIV-1. Supported by ORIP (P51OD011104, P51OD011106), NCATS, and NIAID.
System-Wide Identification of Myeloid Markers of TB Disease and HIV-Induced Reactivation in the Macaque Model of Mtb Infection and Mtb/SIV Co-Infection
Gough et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.777733
HIV is known to catalyze the reactivation of latent tuberculosis (TB) infection. The investigators characterized Mycobacterium tuberculosis (Mtb) and simian immunodeficiency virus (SIV) coinfection using a rhesus macaque model of both sexes, with a focus on pathways relevant to myeloid origin cells (e.g., macrophages). They identified gene signatures of host disease state and progression, as well as clustering algorithms for differentiation between host disease states and relationships among genes. The gene signatures were associated with pathways relevant to apoptosis, adenosine triphosphate production, phagocytosis, cell migration, and type I interferon, which are related to macrophage function. Collectively, these findings suggest that novel macrophage functions influence Mtb infection both with and without SIV coinfection. Supported by ORIP (P51OD011104, P51OD011103, U42OD010442) and NIAID.
Control of Simian Immunodeficiency Virus Infection in Prophylactically Vaccinated, Antiretroviral Treatment–Naive Macaques Is Required for the Most Efficacious CD8 T Cell Response during Treatment with the Interleukin-15 Superagonist N-803
Ellis-Connell et al., Journal of Virology. 2022.
https://www.doi.org/10.1128/jvi.01185-22
Recent evidence suggests that immunotherapeutic agents, such as N-803, could improve the ability of CD8+ T cells to target and destroy cells infected with HIV. In this study, investigators defined the features that are associated with N-803-mediated suppression of simian immunodeficiency virus (SIV) replication in rhesus macaques of both sexes. They hypothesized that preexisting vaccine-elicited CD8+ T cells were required for suppressing replication. Their results indicate that N-803 is most effective in animals with preexisting immunological ability to control SIV replication. These findings support further exploration of N-803 as an immunotherapeutic agent for HIV. Supported by ORIP (P51OD011106) and NIAID.
Distinct Sensitivities to SARS-CoV-2 Variants in Vaccinated Humans and Mice
Walls et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111299
Emergence of SARS-CoV-2 variants necessitates real-time evaluation of their impact on serum neutralizing activity, as a proxy for vaccine efficacy, to inform public health policies and guide vaccine development. The investigators report that vaccinated female BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses toward the SARS-CoV-2 Beta and Gamma variants of concern, compared with humans of both sexes and male nonhuman primates (i.e., rhesus and pigtail macaques). This finding was consistent across several vaccine modalities, doses, antigens, and assays, suggesting caution should be exercised when interpreting serum neutralizing data obtained from mice. Supported by ORIP (P51OD010425, U42OD011123) and NIAID.
Maternal Western-Style Diet Reduces Social Engagement and Increases Idiosyncratic Behavior in Japanese Macaque Offspring
Mitchell et al., Brain, Behavior, and Immunity. 2022.
https://www.doi.org/10.1016/j.bbi.2022.07.004
Evidence points to an association between maternal obesity and risk of early-emerging neurodevelopmental disorders in offspring, yet few preclinical studies have tested for associations between maternal Western-style diet (mWSD) and offspring behavior. Using Japanese macaques, researchers found that mWSD offspring exhibited less proximity to peers and initiated fewer affiliative social behaviors. These outcomes appear to be mediated by increased maternal interleukin-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin. These findings suggest specific prevention and intervention targets for early-emerging neurodevelopmental disorder in humans. Supported by ORIP (P51OD011092), NIMH, and NICHD.
Molecular Insights Into Antibody-Mediated Protection Against the Prototypic Simian Immunodeficiency Virus
Zhao et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32783-2
Most simian immunodeficiency virus (SIV) vaccines have focused on inducing T cell responses alone or in combination with non-neutralizing antibody responses. To date, studies investigating neutralizing antibody (nAb) responses to protect against SIV have been limited. In this study, researchers isolated 12 potent monoclonal nAbs from chronically infected rhesus macaques of both sexes and mapped their binding specificities on the envelope trimer structure. They further characterized the structures using cryogenic electron microscopy, mass spectrometry, and computational modeling. Their findings indicate that, in the case of humoral immunity, nAb activity is necessary and sufficient for protection against SIV challenge. This work provides structural insights for future vaccine design. Supported by ORIP (P51OD011106), NIAID, and NCI.
Isoniazid and Rifapentine Treatment Effectively Reduces Persistent M. tuberculosis Infection in Macaque Lungs
Sharan et al., Journal of Clinical Investigation. 2022.
https://www.doi.org/10.1172/JCI161564
People with HIV and asymptomatic latent tuberculosis (TB) coinfection are at risk of developing active TB symptoms. The Centers for Disease Control and Prevention recommends a weekly dose of isoniazid and rifapentine for 3 months (3HP) for treatment of latent TB infection, but the sterilizing efficacy of the regimen has not been demonstrated previously. Using rhesus macaques of both sexes, researchers evaluated the efficacy of the 3HP regimen in eradicating persistent Mycobacterium tuberculosis infection. They found that treatment reduced the risk of developing active TB but did not establish complete sterilization. This work establishes a new animal model for evaluating the efficacy of different drug regimens. Supported by ORIP (P51OD011133, S10OD028732).
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
Durable Protection Against the SARS-CoV-2 Omicron Variant Is Induced by an Adjuvanted Subunit Vaccine
Arunachalam et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abq4130
Additional SARS-CoV-2 vaccines are needed, owing to waning immunity to the original vaccines and the emergence of variants of concern. A recent study in male rhesus macaques demonstrated durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, an oil-in-water emulsion containing α‑tocopherol. Two immunizations with the vaccine resulted in durable immunity, without cross-reactivity. Further boosting with a version of the vaccine containing the Beta variant or the ancestral RBD elicited cross-reactive immune responses that conferred protection against Omicron challenge. Supported by ORIP (P51OD011104), NCI, and NIAID.
A Clade C HIV-1 Vaccine Protects Against Heterologous SHIV Infection by Modulating IgG Glycosylation and T Helper Response in Macaques
Sahoo et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abl4102
Vaccines for HIV-1 capable of generating a broadly cross-reactive neutralizing antibody response are needed urgently. The researchers tested the protective efficacy of a clade C HIV-1 vaccination regimen in male rhesus macaques. The vaccine was administered either orally using a needle-free injector or via parenteral injection. Significant protection was observed for both vaccination routes following the simian–human immunodeficiency virus (SHIV) challenge, with an estimated efficacy of 68% per exposure. The glycosylation profile of IgG and HIV-resistant helper T cell response contributes to the protection. Supported by ORIP (P51OD011132), NIAID, and NIDCR.