Selected Grantee Publications
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- 42 results found
- Infectious Diseases
- 2022
Phagocytosis by an HIV Antibody Is Associated with Reduced Viremia Irrespective of Enhanced Complement Lysis
Spencer et al., Nature Communications. 2022.
https://doi.org/10.1038/s41467-022-28250-7
Researchers used the bNAb 10E8v4 targeting the HIV Env protein to examine the role of antibody-mediated effector and complement (C′) activity when 10E8v4 was administered prophylactically to rhesus monkeys challenged with simian-human immunodeficiency virus (SHIV). With sub-protective dosing, the researchers found a 78–88% reduction in post-acute viremia that was associated with 10E8v4–mediated phagocytosis. These results suggest that effector functions inherent to unmodified 10E8v4 contribute to therapeutic efficacy against SHIV, while C′ functions do not contribute to efficacy in this context. This research informs the design of bNAb modifications for improving the protective efficacy of this therapeutic approach against HIV. Supported by ORIP (P51OD011092, U42OD023038) and NIAID.
Complex Decay Dynamics of HIV Virions, Intact and Defective Proviruses, and 2LTR Circles Following Initiation of Antiretroviral Therapy
White et al., PNAS. 2022.
https://doi.org/10.1073/pnas.2120326119
In people living with HIV-1 (PLWH) who start antiretroviral therapy (ART), virus in blood decreases rapidly to below detection, but remaining infected cells may become part of the latent reservoir. Researchers investigated viral decay dynamics and identified decay processes with pronounced differences between intact and defective proviruses. Infected cells that survive second-phase decay may down-regulate HIV-1 gene expression and enter the stable latent reservoir. This research provides insight into meaningful latent reservoir markers and mechanisms for elimination of cells with intact viral genomes. Supported by ORIP (R01OD011095) and NIAID.
Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters
Mulka et al., The American Journal of Pathology. 2022.
https://www.doi.org/10.1016/j.ajpath.2021.10.009
To catalyze SARS-CoV-2 research, disease progression was characterized in a robust model. Male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 to track clinical, pathology, virology, and immunology outcomes. Inoculated animals lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses dominated in the lung. These lesions resolved over time. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19. Supported by ORIP (T32OD011089).
Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection
Curtis et al., mSphere. 2022.
https://www.doi.org/10.1128/msphere.00839-21
A tailored, effective HIV vaccine is needed to prevent mother-to-child viral transmission. In nonhuman primate models, infection with simian–human immunodeficiency virus (SHIV) can be prevented by administering broadly neutralizing HIV envelope (Env)–specific antibodies. Investigators tested the efficacy of an intramuscular vaccine regimen against SHIV infection in male and female infant rhesus macaques. The vaccine induced Env-specific antibodies in plasma, with antibody-dependent cellular cytotoxicity and phagocytic function. These antibodies, however, were insufficient for protection against infection. Future studies could focus on improving the breadth of antibody response and improving cell-mediated immunity. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
CAR/CXCR5–T Cell Immunotherapy Is Safe and Potentially Efficacious in Promoting Sustained Remission of SIV Infection
Pampusch et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1009831
HIV and simian immunodeficiency virus (SIV) replication are concentrated within the B cell follicles of secondary lymphoid tissues. In this study, the researchers developed immunotherapeutic chimeric antigen receptor (CAR) T cells that home to follicles and clear SIV-infected cells in a rhesus macaque model. The CAR T cells localized to the follicle, replicated, and interacted directly with infected cells. Most of the treated animals maintained lower viral loads in the blood and follicles, compared to control animals. These findings demonstrate the safety and potential efficacy of this immunotherapy approach for long-term remission of HIV without requiring the lifelong use of antiretroviral therapy. Supported by ORIP (P51OD011106), NIAID, and NHLBI.
Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006–2011)
Balinda et al., Viruses. 2022.
https://www.doi.org/10.3390/v14020334
About 80 percent of heterosexual HIV-1 transmission events are thought to be attributable to a single transmitted/founder (T/F) virus. Studies of HIV T/F viruses could yield valuable insights on transmission and help inform the design of vaccines and therapeutics. To date, most T/F studies have focused on subtype B and C viruses; few studies have focused on subtype D. In this study, the researchers characterized near full-length T/F viral genomes to identify subtype D and A/D recombinants from heterosexual mucosal transmissions in humans. They reported high viral diversity and high pathogenicity, underscoring the importance of matching vaccine designs to the predominant subtypes within populations. Further studies of the full genome sequence could provide additional information for subtyping. Supported by ORIP (P51OD011132) and NIAID.
Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques
Boby et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.835686
Recent studies suggest that people with HIV—particularly those not receiving antiretroviral therapy or those with low CD4 cell counts—are at increased risk of severe illness from SARS‑CoV-2 coinfection. Angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, is likely to play an important role in modulating physiological and pathological events during HIV infection. In this study, the researchers used a rhesus macaque model to characterize the expression profiles of ACE2, other renin-angiotensin system (RAS)–associated genes (AGTR1/2, ADAM17, and TMPRSS2), and inflammatory cytokines (IL-1β, IL-6, and TNF‑α) in the jejunum and lung during simian immunodeficiency virus (SIV) infection. SIV infection was associated with multiple changes in gene expression, including downregulation of ACE2, which could lead to loss of gut homeostasis. Further studies could provide insight on the role of RAS-associated proteins during HIV and SARS-CoV-2 co-infection. Supported by ORIP (P51OD011104) and NIDDK.
Estimation of the In Vivo Neutralization Potency of eCD4Ig and Conditions for AAV-Mediated Production for SHIV Long-Term Remission
Goyal et al., Science Advances. 2022.
https://www.doi.org/10.1126/sciadv.abj5666
The engineered protein eCD4Ig, a synthetic antibody-like inhibitor designed to limit HIV entry into cells, shows promise as an approach to achieve HIV remission without antiretroviral therapy. Researchers used mathematical modeling to characterize in vivo antiviral neutralization of eCD4Ig, as well as possible antibody-dependent cell-mediated cytotoxicity effects, in rhesus macaques infected with simian–human immunodeficiency virus (SHIV) (sex not specified). The research team modeled SHIV and pharmacokinetics dynamics and projected the levels of eCD4Ig needed with a viral vector production approach to suppress SHIV viremia. The data suggest that endogenous, continuous expression of eCD4Ig could overcome the diminishing effects of antidrug antibodies and allow long-term remission of SHIV viremia in nonhuman primates. Supported by ORIP (P51OD011132) and NIAID.
Reduced Infant Rhesus Macaque Growth Rates Due to Environmental Enteric Dysfunction and Association with Histopathology in the Large Intestine
Hendrickson et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-021-27925-x
Researchers characterized environmental enteric (relating to the intestines) dysfunction (EED) among infant rhesus macaques (n=80, both sexes) naturally exposed to enteric pathogens commonly linked to human growth stunting. Despite atrophy and abnormalities observed in the small intestine, poor growth trajectories and low serum tryptophan (an amino acid needed for protein and enzymes) levels were correlated with increased histopathology (microscopic tissue examination for disease manifestation) in the large intestine. This study provides insight into the mechanisms underlying EED and indicates that the large intestine may be an important target for therapeutic intervention. Supported by ORIP (P51OD011092, P51OD011107) and NIGMS.
Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy
Solis-Leal et al., Viruses. 2022.
https://www.doi.org/10.3390/v14010139
The central nervous system (CNS) HIV reservoir contributes to residual neuroimmune activation, which can lead to HIV-associated neurocognitive disorder. Researchers characterized the expression of signaling molecules associated with inflammation in plasma, cerebrospinal fluid, and basal ganglia of Chinese-origin rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV). They reported a correlation between levels of CCL2 in plasma and cerebrospinal fluid, suggesting that researchers could infer the degree of CNS inflammation by testing CCL2 levels in peripheral blood. Overall, these findings provide insight into neuroinflammation and signaling associated with HIV persistence in the CNS. Supported by ORIP (P51OD011104, P51OD011133), NIMH, and NINDS.