Selected Grantee Publications
Liver-Specific Transgenic Expression of Human NTCP In Rhesus Macaques Confers HBV Susceptibility on Primary Hepatocytes
Rust et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937851
This study establishes the first transgenic nonhuman primate model for hepatitis B virus (HBV). Male and female rhesus macaques were engineered to express the human HBV receptor, NTCP (hNTCP), specifically in the liver. Researchers used PiggyBac transposon technology to introduce a liver-specific NTCP transgene into embryos, which were then implanted into surrogate females. The resulting offspring expressed hNTCP in hepatocytes and demonstrated high susceptibility to HBV infection. This model overcomes the species-specific limitations of HBV research, providing a powerful tool for studying HBV biology and evaluating HBV treatments in a clinically relevant model system. Supported by ORIP (P51OD011092), NIDA, and NIAID.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
Immune Restoration by TIGIT Blockade is Insufficient to Control Chronic SIV Infection
Webb et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38775481/
T-cell exhaustion from prolonged upregulation of immune checkpoint receptors (ICR) contributes to immune dysfunction and viral persistence of both human and simian immunodeficiency virus (HIV/SIV) infection. Previous in vitro research has demonstrated the potential use of ICR blockade as a therapeutic. Researchers used a monoclonal antibody targeting humanized T cell immunoreceptor with Ig and ITIM domain (TIGIT) in male and female cynomolgus macaque and female rhesus macaque SIV models, 4–14 years of age. TIGIT blockade was well tolerated, with moderately increased proliferation of T cells and natural killer cells, but a reduction in plasma viral load was not observed. Future research to eliminate SIV should combine ICR blockades with other immunotherapies. Supported by ORIP (P51OD011092), NIAID, and NIMH.
Transiently Boosting Vγ9+Vδ2+ γδ T Cells Early in Mtb Coinfection of SIV-Infected Juvenile Macaques Does Not Improve Mtb Host Resistance
Larson et al., Infection and Immunity. 2024.
https://pubmed.ncbi.nlm.nih.gov/39475292/
Children with HIV have a higher risk of developing tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb). This study utilized juvenile Mauritian cynomolgus macaques to investigate whether enhancing Vγ9+Vδ2+ γδ T cells with zoledronate treatment could improve TB resistance in HIV–TB coinfection. Researchers found that although boosting these immune cells temporarily increased their presence, it did not enhance the macaques’ ability to fight Mtb infection. These findings suggest that solely targeting γδ T cells may not be an effective strategy for improving TB immunity in immunocompromised individuals. These insights are crucial for developing better treatments for HIV–TB coinfections. Supported by ORIP (K01OD033539, P51OD011106) and NIAID.
Potent Broadly Neutralizing Antibodies Mediate Efficient Antibody-Dependent Phagocytosis of HIV-Infected Cells
Snow et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/39466835
This study investigates the role of potent broadly neutralizing antibodies (bNAbs) in mediating antibody-dependent cellular phagocytosis (ADCP) of HIV-infected cells. Researchers developed a novel cell-based approach to assess the ADCP of HIV-infected cells expressing natural conformations of the viral envelope glycoprotein, which allows the virus to infect a host cell. The findings in this study demonstrate that bNAbs facilitate efficient ADCP, highlighting their potential in controlling HIV infection by promoting immune clearance of infected cells. This study provides valuable insights into antibody-mediated immune mechanisms and supports the development of antibody-based therapies and vaccines targeting HIV. Supported by ORIP (P51OD011106) and NIAID.
Phenotypic Characterization of Subtype A and Recombinant AC Transmitted/Founder Viruses From a Rwandan HIV-1 Heterosexual Transmission Cohort
Yue et al., Viruses. 2024.
https://pubmed.ncbi.nlm.nih.gov/39599821
HIV-1 is classified into several phylogenetic groups and subgroups, and to be effective, a vaccine would require broad activity across diverse viral strains. The most widespread group, M, is subdivided into several subgroups (A–D, F–H, J, K, and L). In a previous study, these researchers analyzed cohorts of people with recent or acute HIV infection in Rwanda. Subtype A was the dominant subtype, but a significant number of infections were caused by recombinants of subtypes A and C. This study assessed the characteristics of 16 infectious molecular clones (IMCs) of subtype A or AC recombinant viruses. Viral replication scores varied among the IMCs, and amino acid substitutions in the viral Gag gene were linked to higher replication activity. The sensitivity of different clones to broadly neutralizing antibodies also was assessed. This panel of well-characterized viral IMCs will support studies required to develop an effective HIV-1 vaccine. Supported by ORIP (P51OD011132) and NIAID.
Immune Perturbation Following SHIV Infection Is Greater in Newborn Macaques Than in Infants
Shapiro et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39190496
This study investigates immune perturbation following simian-human immunodeficiency virus (SHIV) infection in newborn and infant male and female rhesus macaques, highlighting significant differences in pathogenesis. Although plasma viremia and lymph node viral DNA were similar, newborns exhibited higher viral DNA levels in gut and lymphoid tissues 6–10 weeks postinfection than infants. Additionally, newborns showed greater immune alterations, with skewed monocyte and CD8+ T-cell profiles and minimal type I interferon responses. These findings suggest age-dependent immunological responses to SHIV and underscore the vulnerability of newborns to HIV-related pathogenesis, providing insights into immune development and pediatric HIV management. Supported by ORIP (P51OD011092, U42OD023038, U42OD010426) and NIAID.
Effect of Metabolic Status on Response to SIV Infection and Antiretroviral Therapy in Nonhuman Primates
Webb et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39115937
This study examines how metabolic health influences the efficacy of antiretroviral therapy (ART). Using lean and obese male rhesus macaques, researchers explored the progression of simian immunodeficiency virus (SIV) infection. Obese macaques with metabolic dysfunction experienced more rapid disease progression and had a diminished response to ART than lean macaques. This study suggests metabolic health plays a significant role in HIV progression and treatment outcomes, highlighting the importance of managing metabolic conditions in people with HIV. Supported by ORIP (P51OD011092, S10OD025002), NIAID, and NIDDK.
Engineered Deletions of HIV Replicate Conditionally to Reduce Disease in Nonhuman Primates
Pitchai et al., Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39116226/
Current antiretroviral therapy (ART) for HIV is limited by the necessity for continuous administration. Discontinuation of ART leads to viral rebound. A therapeutic interfering particle (TIP) was developed as a novel single-administration HIV therapy using defective interfering particles. TIP treatment in two humanized mouse models demonstrated a significant reduction in HIV viral load. TIP intervention was completed 24 hours prior to a highly pathogenic simian immunodeficiency virus (SIV) challenge in a nonhuman primate (NHP) rhesus macaque infant model. Compared to untreated SIV infection, NHPs that received TIP treatment displayed no visible signs of SIV-induced AIDS and exhibited improved seroconversion and a significant survival advantage to the 30-week clinical endpoint. Peripheral blood mononuclear cells isolated from HIV-infected patients showed that TIP treatment reduced HIV outgrowth. This study demonstrates the potential use of a single-administration TIP for HIV treatment. Supported by ORIP (P51OD011092, U42OD010426), NCI, NIAID, and NIDA.
Cytomegalovirus Vaccine Vector-Induced Effector Memory CD4+ T cells Protect Cynomolgus Macaques From Lethal Aerosolized Heterologous Avian Influenza Challenge
Malouli et al., Nature Communications. 2024.
Development of a universal influenza vaccine that protects against seasonal strains and future pandemic influenza viruses is a necessity because of the limited efficacy of current influenza vaccines. Researchers developed a cynomolgus macaque β-herpesvirus cytomegalovirus (CyCMV) vaccine that targets the highly conserved proteins in influenza viruses. Male and female Mauritian-origin cynomolgus macaques (MCM) were vaccinated and boosted with the CyCMV vaccine prior to being challenged with small-particle aerosols containing highly pathogenic avian influenza (HPAI). MCMs receiving the CyCMV vaccine still presented with fever and pulmonary infiltration but demonstrated significant protection against HPAI-induced mortality. Unvaccinated MCMs challenged with HPAI did not survive. Survival was correlated with the magnitude of influenza-specific CD4+ T cells prior to infection. These results demonstrate the efficacy of a novel vaccine that protects against HPAI through a CD4 T cell–mediated response. Supported by ORIP (P51OD010425, P51OD011092) and NIAID.