Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag?TSG101 interaction

The egress of HIV particles from virus-infected cells is accomplished by the recruitment of proteins that normally mediate host cell endocytic functions. This process requires interaction of the HIV Gag protein with the host protein TSG101 (tumor susceptibility gene 101). Here, we report the use of a bacterial reverse two-hybrid system to identify cyclic peptides that interfere with the Gag?TSG101 interaction and the finding that a five amino acid peptide discovered by this approach can disrupt the interaction and consequently inhibit HIV egress. The inhibiting molecule, which was selected from a cyclic peptide library containing 3.2 × 106 members, differs in primary sequence from the interacting sites of either TSG101 or Gag. Addition of cyclic peptide tagged with an HIV Tat sequence, which previously has been shown to enhance protein translocation across plasma membranes, to cultured human cells inhibited the production of virus-like particles (VLPs) by these cells (IC50 of 7 ?M), and this inhibition occurred in the absence of adverse affects on normal endocytic functions mediated by TSG101. A mutant Gag protein not dependent on TSG101 for release was unaffected by the cyclic peptide. Our findings, which suggest that interference with the TSG101?Gag interaction by cyclic peptides may be of practical use in the treatment of HIV infections, identify a specific cyclic peptide that reduces VLP release by this mechanism; they also demonstrate that the efficiency of interference with protein?protein interactions by cyclic peptides can be enhanced by tagging the peptides with translocation-promoting sequences. Collectively our results support the notion that small molecule therapeutics that inhibit specific interactions between viral and host proteins may have general applicability in antiviral therapy.<br/

Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients.

10noRemodeling of the resistance arteries is a hallmark of arterial hypertension and predicts cardiovascular events, but it was unknown whether it could also predict the blood pressure response to adrenalectomy of patients with an aldosterone-producing adenoma. Therefore, we investigated the outcome of adrenalectomy as a function of vascular remodeling in the context of the preoperative features of aldosterone-producing adenoma patients. At 2 referral centers for hypertension, we prospectively measured the media:lumen ratio of small arteries from fat tissue of 50 consecutive aldosterone-producing adenoma patients treated with adrenalectomy. The blood pressure response to adrenalectomy was assessed by considering the blood pressure values and the number and dosages of antihypertensive medications. Adrenalectomy significantly (P<0.001) lowered plasma aldosterone (from 27.3+/-4.9 ng/dL to 8.3+/-11.2 ng/dL), the aldosterone:renin ratio (from 117+/-35 to 11+/-2), and blood pressure (from 163+/-22/98+/-2 mm Hg to 133+/-2/84+/-1 mm Hg), even despite a reduction (from 141+/-14 to 100+/-15; P=0.02) of the score of antihypertensive treatment. It provided cure of hypertension in 30% of the aldosterone-producing adenoma patients, normotension with less antihypertensive therapy in 52%, and improved blood pressure control in the rest. The media:lumen ratio and the known duration of hypertension significantly predicted the blood pressure response to adrenalectomy at univariate and multivariate analyses. Because a long duration of hypertension and/or the presence of vascular remodeling imply lower chances of blood pressure normalization at long-term follow-up postadrenalectomy, these findings emphasize the importance of an early diagnosis of aldosterone-producing adenoma.restrictedrestrictedROSSI GP; BOLOGNESI M; D. RIZZONI; SECCIA TM; PIVA A; PORTERI E; TIBERIO GA; GIULINI SM; AGABITI-ROSEI E; PESSINA ACRossi, Gp; Bolognesi, M; Rizzoni, Damiano; Seccia, Tm; Piva, A; Porteri, Enzo; Tiberio, Guido Alberto Massimo; Giulini, Stefano Maria; AGABITI ROSEI, Enrico; Pessina, A