A5004281940- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- HIV/AIDS Research and Interventions
- Protein Degradation and Inhibitors
- HIV-related health complications and treatments
- Cytomegalovirus and herpesvirus research
- Immune Cell Function and Interaction
- Hepatitis B Virus Studies
- vaccines and immunoinformatics approaches
- RNA Interference and Gene Delivery
- Herpesvirus Infections and Treatments
- Poxvirus research and outbreaks
- interferon and immune responses
- Cannabis and Cannabinoid Research
- Viral Infections and Outbreaks Research
- Bacillus and Francisella bacterial research
- Histone Deacetylase Inhibitors Research
- Supramolecular Chemistry and Complexes
- Crystallography and molecular interactions
- Multiple Myeloma Research and Treatments
- Boron Compounds in Chemistry
- Cell Image Analysis Techniques
- Rabies epidemiology and control
- Tea Polyphenols and Effects
- Viral Infectious Diseases and Gene Expression in Insects
University of North Carolina at Chapel Hill
2019-2025
University of North Carolina Health Care
2019-2024
Office of Infectious Diseases
2020
United States Army Medical Research Institute of Infectious Diseases
2017
University of Maryland, College Park
2016
Harvard University
2016
Massachusetts General Hospital
2016
Committee on Publication Ethics
2016
National Institutes of Health Clinical Center
2016
National Institute of Allergy and Infectious Diseases
2014-2015
Abstract Background The replication-competent human immunodeficiency virus (HIV) reservoir is the major barrier to cure. quantitative viral outgrowth assay (QVOA), gold-standard method quantify HIV, resource intensive, which limits its application in large clinical trials. intact proviral DNA (IPDA) requires minimal cell input relative QVOA and quantifies both defective HIV DNA, latter potentially serving as a surrogate marker for provirus. However, there are limited cross-sectional...
The HIV proviral reservoir is the major barrier to cure. predominantly replication-defective landscape makes measurement of virus that likely cause rebound upon antiretroviral therapy (ART)-cessation challenging. To address this issue, novel assays measure intact proviruses have been developed. DNA assay (IPDA) a high-throughput uses two probes exclude majority defective and determine frequency proviruses, albeit without sequence confirmation. Quadruplex PCR with four (Q4PCR)...
Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting the may require combinatorial approaches. A Jurkat latency model screen IAPi combination partners demonstrated synergistic with bromodomain (BD) and extraterminal domain inhibitors (BETi). Mechanistic investigations CRISPR-CAS9 single-cell...
Abstract The main barrier to HIV cure is a persistent reservoir of latently infected CD4 + T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach target this involves agents reactivate latent proviruses followed by direct clearance expressing induced viral antigens immune effector and immunotherapeutics. We previously showed AZD5582, an antagonist inhibitor apoptosis proteins mimetic the second...
Abstract Background The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected vitro. HIV-specific (HXTCs) be expanded ex have been safely administered people with HIV (PWH) on antiretroviral therapy. Methods Six PWH received infusions of 2 × 107 HXTCs/m² VOR 400 mg, 3 10 VOR. frequency persistent by multiple assays including quantitative viral outgrowth assay (QVOA) resting CD4+ was measured...
Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses these drug candidates. Here, proof-of-concept studies demonstrate the potential our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as solubilizing agent insoluble drugs. M1 did not induce significant rates mutations in...
Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell immunotherapeutic, on reservoir. HIV+, stably treated participants in whom resting CD4+ T cell-associated RNA (rca-RNA) increased after VOR exposure ex vivo received 4 doses AGS-004 every 3 weeks, followed by 72 hours for 30 days, then cycle repeated. Change VOR-responsive host gene expression, HIV-specific...
Abstract We tested the combination of a broadly neutralizing HIV antibody with latency reversal agent vorinostat (VOR). Eight participants received 2 month-long cycles VRC07-523LS VOR. Low-level viremia, resting CD4+ T-cell–associated RNA (rca-RNA) was measured, and intact proviral DNA assay (IPDA) quantitative viral outgrowth (QVOA) were performed at baseline posttreatment. In 3 participants, IPDA QVOA declines accompanied by significant rca-RNA. However, no or clearly exceeded variance...
Abstract HIV cure strategies that aim to induce viral reactivation for immune clearance leverage latency reversal agents modulate host pathways which directly or indirectly facilitate reactivation. Inhibition of BET (bromo and extra-terminal domain) family member BRD4 reverses latency, but enthusiasm the use inhibitors in studies is tempered by concerns over inhibition other members dose-limiting toxicities oncology trials. Here we evaluated potential bivalent chemical degraders targeted as...
Calabadion 2 is a new drug-encapsulating agent. In this study, the authors aim to assess its utility as an agent reverse general anesthesia with etomidate and ketamine facilitate recovery.To evaluate effect of calabadion on recovery, studied response rats after continuous bolus intravenous or intramuscular administration. The measured electroencephalographic predictors depth (burst suppression ratio total power), functional mobility impairment, blood pressure, toxicity.Calabadion...
Persistent HIV infection of long-lived resting CD4 T cells, despite antiretroviral therapy (ART), remains a barrier to cure. Women have more robust type 1 interferon response during relative men, contributing lower initial plasma viremia. As viremia acute is associated with reduced frequency latent infection, we hypothesized that women on ART would compared men.ART-suppressed, seropositive (n = 22) were matched 1:1 22 39 ART-suppressed men. We also the all adjusting for age and race as...
ABSTRACT HIV cure strategies that aim to induce viral reactivation for immune clearance leverage latency reversal agents modulate host pathways which directly or indirectly facilitate reactivation. Inhibition of bromo and extra-terminal domain (BET) family member BRD4 reverses latency, but enthusiasm the use BET inhibitors in studies is tempered by concerns over inhibition other members dose-limiting toxicities oncology trials. Here, we evaluated potential bivalent chemical degraders...
Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared studied. The inherent solubilities M2C2 (68 mm) M2C4 (196 are higher than analogue with a )3 (M2, 14 studied previously. (1) H NMR dilution experiments show do not self-associate water, which enables use as excipients. We used phase solubility diagrams (PSDs) to compare capacities M2,...
Influenza viruses are a threat to global public health resulting in ~500,000 deaths each year. Despite an intensive vaccination program, influenza infections remain recurrent, yet unsolved problem. Secondary bacterial frequently complicate during seasonal outbreaks and pandemics, increased morbidity mortality. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is associated with these co-infections, the 2009 pandemic. Damage alveolar epithelium major contributor severe...
Human immunodeficiency virus (HIV) infection remains incurable due to the persistence of a viral reservoir despite antiretroviral therapy (ART). Cannabis (CB) use is prevalent amongst people with HIV (PWH), but impact CB on latent has not been investigated.
Understanding the interplay between HIV reservoir and host immune system may yield insights into persistence during antiretroviral therapy (ART) inform strategies for a cure. Here, we applied machine learning (ML) approaches to cross-sectional high-parameter immunology data in order characterize host–reservoir associations generate new hypotheses about biology. High-dimensional immunophenotyping, quantification of HIV-specific T cell responses, measurement genetically intact total proviral...
The Syrian golden hamster has been increasingly used to study viral hemorrhagic fever (VHF) pathogenesis and countermeasure efficacy. As VHFs are a global health concern, well-characterized animal models essential for both the development of therapeutics vaccines as well increasing our understanding molecular events that underlie pathogenesis. However, paucity reagents or platforms available studying hamsters at level limits ability extract biological information from this important model....
The eradication of HIV infection is difficult to achieve because stable viral reservoirs. Here, we show that crotonylation enhances AZD5582-induced noncanonical NF-κB (ncNF-κB) signaling, further augmenting latency reversal in Jurkat and U1 cell line models latency, latently infected primary CD4+ T cells resting isolated from people living with HIV. Crotonylation upregulated the levels active p52 subunit following AZD5582. Biochemical analyses suggest ubiquitin E3 ligase TRIM27 involved...
Bacillus anthracis, the etiological agent of anthrax, is listed as a category A biothreat by United States Centers for Disease Control and Prevention. The virulence organism due to expression two exotoxins capsule, which interfere with host cellular signaling, alter water homeostasis inhibit phagocytosis pathogen, respectively. Concerns regarding past possible future use B. anthracis bioterrorism have resulted in an impetus develop more effective protective measures therapeutics. In this...
Lifelong treatment is required for people living with HIV as current antiretroviral therapy (ART) does not eradicate infection. Latently infected cells are essentially indistinguishable from uninfected and cannot be depleted by currently available approaches. This study evaluated antibody mediated transient CD4 + T cell depletion a strategy to reduce the latent reservoir. Anti-CD4 antibodies effectively in peripheral blood tissues of humanized mice. We then demonstrate that antibody-mediated...
ABSTRACT Limited cellular levels of the HIV transcriptional activator Tat are one contributor to proviral latency that might be targeted in cure strategies. We recently demonstrated lipid nanoparticles containing tat mRNA induce expression primary CD4 T cells. Here, we sought further characterize context several benchmark reversal agents (LRAs), including inhibitor apoptosis protein antagonists (IAPi), bromodomain and extra-Terminal motif inhibitors (BETi), histone deacetylase (HDACi)....