RESUMEN
Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation-positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4+ T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.
Asunto(s)
Infecciones por VIH , VIH-1 , Animales , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , VIH-1/fisiología , Proteínas del Virus de la Inmunodeficiencia Humana , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Nucleares/metabolismo , ARN , Factores de Transcripción/metabolismo , Activación Viral , Latencia del VirusRESUMEN
We present the case of a 7-month-old infant undergoing thoracotomy and left lower lobe lobectomy who experienced a significant complication related to lung isolation with a bronchial blocker. Despite good isolation and seemingly appropriate positioning, the bronchial blocker became entrapped within the staple line at the bronchial stump. Fortunately, the surgeon was able to free the blocker. Going forward, we recommend clinicians be vigilant in positioning the blocker just distal to the carina in all cases and, further, consider retracting the blocker into the trachea before surgical intervention on the airway to avoid inadvertent entrapment of the device.
