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Camptothecin analogs as "block and lock" agents for HIV

open

NIAID - National Institute of Allergy and Infectious Diseases

Project summary/abstract Despite effective antiretroviral therapy (ART), people with HIV (PWH) continue to have chronic inflammation and comorbidities driven by low-level viral transcription from integrated HIV proviruses. Silencing this residual HIV activity could reduce immune activation and improve long-term health. Our long-term goal is to develop therapies that suppress HIV expression and inflammation in PWH on ART. Topotecan (TPT), a Camptothecin analog that inhibits Topoisomerase I, potently suppresses HIV transcription in latently infected T cells. Notably, TPT appears to inhibit HIV independent of its Topoisomerase I activity, suggesting an alternative mechanism of action. We will evaluate new Camptothecin analogs as HIV “block- and-lock” agents. Our central hypothesis is that these compounds can stably suppress HIV without harming host cells. We will pursue three aims: 1) Determine the mechanisms by which TPT inhibits HIV gene expression; 2) Identify new Camptothecin analogs with HIV inhibitory function; 3) Determine the longevity of Camptothecin analog-induced HIV suppression and validate their function using samples from PWH ex vivo. First, we will define how TPT blocks HIV by mapping epigenetic changes at the viral promoter (via CUT&RUN), testing Tat dependence, and assessing post-transcriptional effects like RNA stability and nuclear export (Aim 1). Second, we will screen Camptothecin analogs—with and without Topoisomerase I activity—to identify compounds that suppress HIV at low doses without cytotoxicity. Lead candidates will be validated in primary cells, and their mechanisms and off-target effects will be characterized (Aim 2). Third, we will test whether these compounds can durably silence HIV in latency models and in cells from PWH ex vivo (Aim 3). Completion of these studies will clarify how Camptothecin analogs suppress HIV and assess their therapeutic potential. We expect this work will enable the development of novel “block-and-lock” drugs that reduce persistent inflammation and improve health outcomes in PWH on ART.

Up to $719K
2031-01-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Cardiac MRI Phenotyping of Coronary Microvascular Dysfunction

open

NHLBI - National Heart Lung and Blood Institute

Project Summary Angina is one of the most common symptoms prompting coronary angiography, yet up to 50% of patients are found to have no significant obstructive coronary artery disease (CAD). Many of these individuals continue to experience chest pain without a clear diagnosis. In a substantial proportion of cases, symptoms are attributable to coronary microvascular dysfunction (MVD), an increasingly recognized contributor to myocardial ischemia, heart failure with preserved ejection fraction (HFpEF), obesity, and diabetes. Despite its high prevalence, MVD remains underdiagnosed and challenging to monitor noninvasively. Invasive coronary function testing (CFT) is the gold standard but is technically complex, carries procedural risk, and is limited to specialized centers. While positron emission tomography (PET) enables non-invasive quantification of myocardial blood flow (MBF) and myocardial perfusion reserve (MPR), its utility is constrained by cost, limited availability, radiation exposure, and moderate spatial resolution. Cardiac magnetic resonance (CMR) offers a promising, widely accessible alternative. Recent advances in quantitative perfusion mapping, Artificial Intelligence-driven image enhancement, and multiparametric tissue characterization have transformed stress CMR into a powerful tool for assessing perfusion and myocardial health with high spatial resolution. These capabilities position CMR to play a central role in the diagnosis and monitoring of MVD. This proposal leverages state-of-the-art CMR technology, cross-modality validation, invasive testing, and mechanistic phenotyping to: • Define and validate CMR-based diagnostic criteria for MVD using invasive CFT as the reference standard. • Evaluate the correlation and comparative diagnostic accuracy of CMR- versus PET-derived MBF and MPR for detecting MVD. • Assess whether GLP-1 receptor agonist (GLP-1RA) therapy improves coronary microvascular function independent of weight loss, using bariatric surgery as a comparator and serial quantitative CMR for longitudinal assessment. This work addresses a critical unmet need for non-invasive diagnostic tools and treatment monitoring in MVD, with the potential to expand precision cardiovascular care for an overlooked yet high-risk population.

Up to $848K
2031-03-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

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