Selected Grantee Publications
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.
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.
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.
Innate Immune Regulation in HIV Latency Models
Olson et al., Retrovirology. 2022.
https://www.doi.org/10.1186/s12977-022-00599-z
Researchers are interested in developing therapeutic approaches to target latent HIV reservoirs, which are unaffected by antiretroviral therapy. Previous studies suggest that HIV latency might be related to viral RNA sensing, interferon (IFN) signaling, and IFN-stimulated gene (ISG) activation. In this study, the researchers evaluated responses to stimulation by retinoic acid–inducible gene I agonists and IFN in multiple CD4+ T cell line models for HIV latency. The models represented various aspects of latent infection and viral control. Several of the cell lines demonstrated reduced ISG induction, suggesting that long-term latency might be related to dysregulation of the downstream IFN response. These effects likely reflect transcriptional changes occurring within a core set of ISGs and altering IFN responses. Additional studies could provide insight into the functions of these ISGs in HIV latency. Supported by ORIP (P51OD010425), NCATS, and NIAID.
Safety and Antiviral Activity of Triple Combination Broadly Neutralizing Monoclonal Antibody Therapy Against HIV-1: A Phase 1 Clinical Trial
Julg et al., Nature Medicine. 2022.
https://www.doi.org/10.1038/s41591-022-01815-1
Previous evidence suggests that at least three broadly neutralizing antibodies (bNAbs) targeting different epitope regions are needed for robust treatment and control of HIV. The investigators evaluated the safety, tolerability, and pharmacokinetics of PGDM1400, an HIV-1 V2-glycan–specific antibody, in a first-in-human trial. The primary endpoints were safety, tolerability, pharmacokinetics, and antiviral activity. The trial met the prespecified endpoints in male and female adults. These data will help advance understanding of the capabilities, limitations, and future role of bNAb combinations in HIV prevention and care. Supported by ORIP (R01OD024917), NIAID, and NCATS.