HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal. Here we report the comparative performance of lead bryologs, including their effects in reducing cell surface expression of HIV entry receptors, inducing proinflammatory cytokines, inhibiting short-term HIV replication, and synergizing with histone deacetylase inhibitors to reverse HIV latency. These data provide unique insights into structure-function relationships between A- and B-ring bryolog modifications and activities in primary cells, and suggest that bryologs represent promising leads for preclinical advancement.

Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension ( PH ). However, the role of low‐density lipoprotein receptor ( LDL ‐R) in PH is not known. Methods and Results We examined the role of LDL ‐R in the development of PH and determined the efficacy of high‐density lipoprotein mimetic peptide 4F in mitigating PH . Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL ‐R null ( LDL ‐R knockout) mice (12–15 months old) were fed chow, Western diet ( WD ), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real‐time quantitative reverse transcription–polymerase chain reaction, and histological analysis were performed. The effect of LDL ‐R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL ‐R and CD 36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL , E06 immunoreactivity, and plasma oxidized LDL / LDL ratio. LDL ‐R knockout mice on WD developed PH , right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL ‐R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL ‐R in lungs and increased oxidized LDL in lungs and plasma. WD‐ fed LDL ‐R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL ‐R and oxidized lipids in PH .