Selected Grantee Publications
- Clear All
- 9 results found
- Infectious Diseases
- R01
- Genetics
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.
Antiretroviral Therapy Reveals Triphasic Decay of Intact SIV Genomes and Persistence of Ancestral Variants
Fray et al., Cell Host & Microbe. 2023.
https://doi.org/10.1016/j.chom.2023.01.016
Antiretroviral therapy (ART) halts HIV-1 replication but is not curative; a pool of latently infected CD4+ T cells persists, and viremia rapidly rebounds if ART is stopped. Using an intact proviral DNA assay, researchers characterized quantitative and qualitative changes in CD4+ T cells for 4 years following ART initiation in rhesus macaques of both sexes. They found that viruses replicating at ART initiation had mutations conferring antibody escape, and sequences with large numbers of antibody escape mutations became less abundant at later time points. Together, these findings reveal that the population of simian immunodeficiency virus (SIV)–infected CD4+ T cells is dynamic and provide a framework for evaluating and interpreting intervention trials. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
AZD5582 Plus SIV-Specific Antibodies Reduce Lymph Node Viral Reservoirs in Antiretroviral Therapy–Suppressed Macaques
Dashti et al., Nature Medicine. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579098/
Researchers are interested in targeting the HIV reservoir via a latency reversal and clearance approach. Previously, investigators demonstrated that AZD5582 induces systemic latency reversal in rhesus macaques and humanized mice, but a consistent reduction in the viral reservoir was not observed. In the current study, they combined AZD5582 with four simian immunodeficiency virus (SIV)–specific rhesus monoclonal antibodies using rhesus macaques of both sexes. They reported a reduction in total and replication-competent SIV DNA in lymph node–derived CD4+ T cells in the treated macaques. These findings provide proof of concept for the potential of the latency reversal and clearance HIV cure strategy. Supported by ORIP (P51OD011132, R01OD011095), NIAID, NCI, and NHLBI.
Biphasic Decay of Intact SHIV Genomes Following Initiation of Antiretroviral Therapy Complicates Analysis of Interventions Targeting the Reservoir
Kumar et al., PNAS. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/
The latent HIV-1 reservoir persists with antiretroviral therapy (ART), and assays for quantifying intact proviruses in nonhuman primate models are needed. Researchers used a simian–human immunodeficiency virus (SHIV) intact proviral DNA assay to describe viral decay during the first year of ART in female rhesus macaques. Their results suggest that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase and a slower second phase. These findings can provide insight for future studies using SHIV models, as well as new cure interventions. Supported by ORIP (R01OD011095) and NIAID.
The Latent Reservoir of Inducible, Infectious HIV-1 Does Not Decrease Despite Decades of Antiretroviral Therapy
McMyn et al., The Journal of Clinical Investigation. 2023.
https://www.doi.org/10.1172/JCI171554
Antiretroviral therapy (ART) does not eliminate the latent HIV reservoir, but it is unknown whether sustained reservoir decay occurs with long-term ART. Researchers used a quantitative viral outgrowth assay, an intact proviral DNA assay, and proviral sequencing to characterize the latent reservoir in men and women with HIV who had maintained suppression of viral replication on ART for 14 to 27 years. They found that the reservoir decay did not continue with long-term ART. Further studies could provide insight into the mechanism underlying these findings. These results reinforce the need for lifelong ART and indicate that the reservoir remains a major barrier to an HIV-1 cure. Supported by ORIP (R01OD011095), NIAID, and NIDCR.
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.
A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies
McCann et al., Journal of Experimental Medicine. 2021.
https://doi.org/10.1084/jem.20201908
HIV-specific CD8+ T cells partially control viral replication but rarely provide lasting protection due to immune escape. Investigators showed that engrafting NSG mice with memory CD4+ T cells from HIV+ donors enables evaluation of autologous T cell responses while avoiding graft-versus-host disease. Treating HIV-infected mice with clinically relevant T cell products reduced viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an Interleukin-15 superagonist but was ultimately limited by the pervasive selection of escape mutations, recapitulating human patterns. This “participant-derived xenograft” model provides a powerful tool for developing T cell-based therapies for HIV. Supported by ORIP (R01OD011095), NIAID, NIDA, NIMH, NINDS, and NCATS.
The SARS-CoV-2 Receptor and Other Key Components of the Renin-Angiotensin-Aldosterone System Related to COVID-19 are Expressed in Enterocytes in Larval Zebrafish
Postlethwait et al., Biology Open. 2021.
https://bio.biologists.org/content/10/3/bio058172.article-info
Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II and serves as the SARS-CoV-2 receptor. To exploit zebrafish to understand the relationship of RAAS to COVID-19, the group conducted genomic and phylogenetic analyses. Results identified a type of enterocyte as the expression site of zebrafish orthologs of key RAAS components, including the SARS-CoV-2 co-receptor. Results identified vascular cell subtypes expressing Ang II receptors and identified cell types to exploit zebrafish as a model for understanding COVID-19 mechanisms. Supported by ORIP (R24OD026591, R01OD011116), NIGMS, NICHD.
Persistence of Viral RNA in Lymph Nodes in ART-suppressed SIV/SHIV-Infected Rhesus Macaques
Cadena et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-21724-0
The long-lived viral reservoir is a key obstacle to curing HIV/AIDS, yet the features of that reservoir during antiretroviral therapy (ART) remain poorly understood. Researchers undertook a comprehensive analysis of the SIV/SHIV reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Their findings support a model in which the tissue viral reservoir is rapidly and broadly seeded early during acute infection. Viral RNA persists lymphoid tissues despite a long period of suppressive ART. Therefore, viral latency does not appear to be universally transcriptionally silent; the reservoir may include a spectrum of latency depths. Supported by ORIP (R01OD024917) and NIAID.