Research Question / QI Topic: Multimodal lifestyle interventions are the first line for obesity treatment with the Shared Medical Appointment (SMA) model offering a framework for educating groups of patients sharing common diagnoses, combined with individualized medication management. Despite their effectiveness in promoting weight loss and improving metabolic outcomes, the influence of lifestyle medicine SMAs on psychosocial and lifestyle outcomes remains underexamined. This study investigates the extent to which participation in a virtual, lifestyle medicine-focused SMA program affects these important factors. Data and Methods: Data comes from a retrospective chart review of 172 patients enrolled in the Supervised Lifestyle and Integrative Medicine (SLIM) program, a virtual, lifestyle medicine-focused, SMA program for weight management. Eligible patients included individuals 18 years of age or older and with a body mass index (BMI) of at least 30 kg/m2 or 27 kg/m2 with at least one weight-related comorbidity. Patients completed self-reported questionnaires at baseline and after the clinical program that assessed psychosocial, lifestyle, and behavioral outcomes. Paired sample analysis will be utilized to describe differences in self-efficacy (Self-efficacy to Manage Chronic Disease Questionnaire), perceived stress levels (Perceived Stress Scale-4 Questionnaire (PSS-4)), and mindfulness (Five Facet Mindfulness Questionnaire (FFMQ). Changes in patients’ dietary quality pre and post-clinical intervention will also be analyzed. Results: We hypothesize that participants will show enhanced self-efficacy, stress management, and mindfulness, along with healthier eating habits post-program. Significance: Our study elucidates the impact of a lifestyle-medicine-focused virtual SMA program on psychosocial and lifestyle factors. This study makes a meaningful contribution to the growing body of literature on SMAs for obesity management.

Low level HIV transcription during modern antiretroviral therapy (ART) in persons with HIV is linked to residual inflammation and associated diseases, like cardiovascular disease and cancer. The "block and lock" approach to hold HIV in a state of deep latency may help decrease residual inflammation in a person with HIV on ART and thus improve health. A camptothecin analog topotecan (TPT) was previously implicated as an inhibitor of active HIV replication. Using an in vitro primary T cell model of HIV latency, we demonstrated that (i) TPT reduces HIV transcriptional activity in latently infected cells; (ii) downregulation of HIV RNA by TPT cannot be reversed by latency reversing agents; (iii) several primary and secondary mechanism of action of TPT may be involved in control of HIV replication; (iv) regulation of HIV RNA by TPT is dependent on splicing complexity; (v) increase in proportion of unspliced HIV transcripts was facilitated by intron retention and upregulation of splicing factors, specifically SRSF6, by TPT. Although high TPT dosing (10 μM) was needed to achieve the observed effects, viability of primary CD4⁺ T cells was not greatly affected. Because toxicity can be observed with TPT in persons with cancer, TPT is unlikely to be used as an anti-HIV agent in clinic, but our study provides proof that camptothetin has "block and lock" activity. Other camptothetin analogs, which are less toxic than TPT, should be designed and tested as HIV "block and lock" agents. IMPORTANCE HIV survives in a state of very low activity, called latency, for long periods in persons with HIV on antiretroviral therapy. This low activity of HIV is linked to residual inflammation and associated diseases, such as heart disease and cancer. New strategies are being explored to further silence the HIV provirus and suppress residual inflammation. This study provides strong evidence that the camptothetin analog, Topotecan, can reduce residual activity of HIV in an experimental model of HIV latency. While Topotecan itself is likely not suitable for use in the clinic due to its toxicity, other camptothetin analogs should be designed and investigated as "block and lock" agents.

Background

The latent HIV reservoir represents the major barrier to a cure. One curative strategy is targeting diseased cells for elimination based on biomarkers that uniquely define these cells. Single-cell RNA sequencing (scRNA-seq) has enabled the identification of gene expression profiles associated with disease at the single-cell level. Because HIV provirus in many cells during latency is not entirely silent, it became possible to determine gene expression patterns in a subset of cells latently infected with HIV.

Objective

The primary objective of this study was the identification of the gene expression profiles of single latently infected CD4+ T cells using scRNA-seq. Different conditions of latency establishment were considered. The identified profiles were then explored to prioritize the identified genes for future experimental validation.

Methods

To facilitate gene prioritization, three approaches were used. First, we characterized and compared the gene expression profiles of HIV latency established in different environments: in cells that encountered an activation stimulus and then returned to quiescence, and in resting cells that were infected directly via cell-to-cell viral transmission from autologous activated, productively infected cells. Second, we characterized and compared the gene expression profiles of HIV latency established with viruses of different tropisms, using an isogenic pair of CXCR4- and CCR5-tropic viruses. Lastly, we used proviral expression patterns in cells from people with HIV to more accurately define the latently infected cells in vitro.

Results

Our analyses demonstrated that a subset of genes is expressed differentially between latently infected and uninfected cells consistently under most conditions tested, including cells from people with HIV. Our second important observation was the presence of latency signatures, associated with variable conditions when latency was established, including cellular exposure and responsiveness to a T cell receptor stimulus and the tropism of the infecting virus.

Conclusion

Common signatures, specifically genes that encode proteins localized to the cell surface, should be prioritized for further testing at the protein level as biomarkers for the ability to enrich or target latently infected cells. Cell- and tropism-dependent biomarkers may need to be considered in developing targeting strategies to ensure that all the different reservoir subsets are eliminated.