Selected Grantee Publications
- Clear All
- 127 results found
- Nonhuman Primate Models
- HIV/AIDS
CD8+ Lymphocytes Do Not Impact SIV Reservoir Establishment under ART
Statzu et al., Nature Microbiology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894752/
The HIV-1 latent reservoir has been shown to persist following antiretroviral therapy (ART), but the mechanisms underlying the establishment and maintenance of the reservoir are not fully understood. Using rhesus macaques of both sexes, investigators examined the effects of CD8+ T cells on formation of the latent reservoir with simian immunodeficiency virus (SIV) infection. They found that CD8+ T cell depletion resulted in slower decline of viremia but did not change the frequency of infected CD4+ T cells in the blood or lymph nodes. Additionally, the size of the persistent reservoir was unchanged. These findings suggest that the viral reservoir is established largely independent of SIV-specific cytotoxic T lymphocyte control. Supported by ORIP (P51OD011132), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
Duration of Antiretroviral Therapy Impacts the Degree of Residual SIV Infection in the Gut in Long‐Term Non‐Progressing Chinese Rhesus Macaques
Solis-Leal et al., Journal of Medical Virology. 2023.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.28185
HIV and simian immunodeficiency virus (SIV) reservoirs have been shown to persist with antiretroviral therapy (ART), particularly in the gut‐associated lymphoid tissues in the intestine. The effects of ART on the reservoir size, however, had not been explored fully. In this study, researchers used male Chinese‐origin rhesus macaques to assess the effects of long- and short-term ART on gut infection—across segments of the small and large intestines—in long‐term non‐progressors (LTNPs). They reported that although ART does not eliminate SIV in LTNPs, a longer ART period dramatically reduces SIV infection and diversity in the gut. Further studies are needed to better understand the reduction of HIV gut reservoirs in this context. Supported by ORIP (P51OD011133, P51OD011104), NIAID, NIMH, and NINDS.
Recombinant Simian Varicella Virus–Simian Immunodeficiency Virus Vaccine Induces T and B Cell Functions and Provides Partial Protection Against Repeated Mucosal SIV Challenges in Rhesus Macaques
Pahar et al., Viruses. 2022.
https://www.doi.org/10.3390/v14122819
An effective vaccine is needed urgently to control the global HIV epidemic completely by 2030. Recombinant simian varicella virus (rSVV) vaccines expressing SIV antigens offer a potential new approach in the evaluation of HIV vaccine candidates. Building on their previous findings, the investigators induced systemic and mucosal immune responses with live, attenuated rSVV vaccinations followed by SIV group–specific antigen and SIV envelope protein boosts in female rhesus macaques treated with repeated intravaginal SIV challenges. Their findings demonstrate that the vaccination with protein boosts induces a 37.5% efficacy rate against pathogenic SIV challenge by generating mucosal memory, virus‑specific neutralizing antibodies, binding antibodies, and polyfunctional T cell responses. Supported by ORIP (P51OD011104) and NIAID.
Transient T Cell Expansion, Activation, and Proliferation in Therapeutically Vaccinated Simian Immunodeficiency Virus–Positive Macaques Treated with N-803
Harwood et al., Journal of Virology. 2022.
https://www.doi.org/10.1128/jvi.01424-22
Many HIV vaccine strategies induce neutralizing antibodies and CD8+ T cells, but more information on these protective immune responses is needed. Researchers hypothesized that CD8+ T cells elicited by vaccination during antiretroviral therapy (ART) would be recalled and boosted by treatment with N-803 after ART discontinuation. They tested this approach in male Mauritian cynomolgus macaques infected with simian immunodeficiency virus. The regimen enhanced the frequency of Gag-specific lymphocytes with phenotypes associated with activation, proliferation, and memory in the peripheral blood and lymph nodes of vaccinated animals. These results help demonstrate N-803’s potential as an immunomodulatory agent for treatment of HIV. Supported by ORIP (P51OD011106) and NIAID.
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.
Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus–Infected Pigtail Macaques (Macaca nemestrina) as a Model of Psychosocial Stress in Acute HIV Infection
Castell et al., Psychosomatic Medicine. 2022.
https://www.doi.org/10.1097/PSY.0000000000001132
Psychosocial stress is associated with immune system dysregulation and worsened clinical outcomes in people with HIV. Investigators performed a retrospective analysis of acute simian immunodeficiency virus (SIV) infection of male pigtail macaques to compare the innate immune responses of social and single housing. The singly housed macaques showed reduced expansion of classical and intermediate monocytes, prolonged thrombocytopenia, and suppression of platelet activation during the first 2 weeks after inoculation. These findings indicate that psychosocial stress might induce clinically significant immunomodulatory effects in the innate immune system during acute SIV infection. Supported by ORIP (P40OD013117, K01OD018244, T32OD011089, U42OD013117), NIAID, NIMH, and NINDS.
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.
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).