Kaposi's sarcoma herpesvirus activates the hypoxia response to usurp HIF2α-dependent translation initiation for replication and oncogenesis

Kaposi's sarcoma herpesvirus (KSHV) is an angiogenesis-inducing oncovirus whose ability to usurp the oxygen-sensing machinery is central to its oncogenicity. By upregulating the hypoxia-inducible factors (HIFs), KSHV reprograms infected cells to a hypoxia-like state, triggering angiogenesis. Here we identify a link between KSHV replicative biology and oncogenicity by showing that KSHV's ability to regulate HIF2α levels and localization to the endoplasmic reticulum (ER) in normoxia enables translation of viral lytic mRNAs through the HIF2α-regulated eIF4E2 translation-initiation complex. This mechanism of translation in infected cells is critical for lytic protein synthesis and contributes to KSHV-induced PDGFRA activation and VEGF secretion. Thus, KSHV regulation of the oxygen-sensing machinery allows virally infected cells to initiate translation via the mTOR-dependent eIF4E1 or the HIF2α-dependent, mTOR-independent, eIF4E2. This “translation initiation plasticity” (TRIP) is an oncoviral strategy used to optimize viral protein expression that links molecular strategies of viral replication to angiogenicity and oncogenesis.Fil: Méndez Solís, Omayra. University of Miami; Estados UnidosFil: Bendjennat, Mourad. University of Miami; Estados UnidosFil: Naipauer, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. University of Miami; Estados UnidosFil: Theodoridis, Phaedra R.. University of Miami; Estados UnidosFil: Ho, J.J. David. University of Miami; Estados UnidosFil: Verdun, Ramiro E.. University of Miami; Estados UnidosFil: Hare, Joshua M.. University of Miami; Estados UnidosFil: Cesarman, Ethel. Weill Cornell Medicine; Estados UnidosFil: Lee, Stephen. University of Miami; Estados UnidosFil: Mesri, Enrique Alfredo. University of Miami; Estados Unido

Blood pressure normalization in a large population of hypertensive patients treated with perindopril/indapamide combination: results of the OPTIMAX trial.

OBJECTIVE: To determine if the fixed-dose perindopril/indapamide combination (Per/Ind) normalizes blood pressure (BP) in the same fraction of hypertensive patients when treated in everyday practice or in controlled trials. METHODS: In this prospective trial, 17 938 hypertensive patients were treated with Per 2 mg/Ind 0.625 mg for 3-6 months. In Group 1 Per/Ind was initiated in newly diagnosed patients (n = 7032); in Group 2 Per/Ind replaced previous therapy in patients already treated but having either their BP still uncontrolled or experiencing side-effects (n = 7423); in Group 3 Per/Ind was added to previous treatment in patients with persistently high BP (n = 3483). BP was considered normalized when < or = 140/90 mm Hg. A multivariate analysis for predictors of BP normalization was performed. RESULTS: Subjects were on average 62 years old and had a baseline BP of 162.3/93.6 mm Hg. After treatment with Per/Ind, BP normalization was reached in 69.6% of patients in the Initiation group, 67.5% in the Replacement Group, and 67.4% in the Add-on Group (where patients were more frequently at risk, diabetic, or with target organ damage). Mean decreases in systolic BP of 22.8 mm Hg and in diastolic BP of 12.4 mm Hg were recorded. CONCLUSIONS: This trial was established to reflect everyday clinical practice, and a treatment strategy based on the Per/Ind combination, administered as initial, replacement, or add-on therapy, led to normalization rates that were superior to those observed in Europe in routine practice. These results support recent hypertension guidelines which encourage the use of combination therapy in the management of arterial hypertension

Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach.

OBJECTIVE: To compare the efficacy and the tolerability of three different strategies in the treatment of hypertension (low-dose combination, sequential monotherapy and stepped-care). DESIGN: Hypertensive patients were randomized to a 9-month treatment with the aim to lower blood pressure below 140/90 mmHg. Treatment adjustments were allowed at months 3 and 6. The study was discontinued for patients with normal blood pressure at month 6. In the 'low-dose combination' group, perindopril (2 mg) and indapamide (0.625 mg) were first administered with the possibility to increase the doses in two steps up to respectively, 4 and 1.25 mg. In the 'sequential monotherapy' group, the treatment was initiated with atenolol (50 mg), replaced if necessary by losartan (50 mg), and then by amlodipine (5 mg). In the 'stepped-care' group, valsartan, was given first at a 40 mg dose, then at a 80 mg dose, to be co-administered finally if needed with hydrochlorothiazide, 12.5 mg. All study tablets were encapsulated to conceal their identity and had to be taken once a day. PATIENTS: Patients with uncomplicated essential hypertension were recruited (n = 180 in the 'low-dose combination' group, n = 176 in the 'sequential monotherapy' group and n = 177 in the 'stepped-care' group). RESULTS: The percentage of patients having achieved the target blood pressure was significantly greater in the 'low-dose combination' group (62%) than in the 'sequential monotherapy' (49%, P = 0.02) and the 'stepped-care' group (47%, P = 0.005). The percentage of patients having normalized their blood pressure without experiencing drug-related adverse events was also significantly higher in the 'low-dose combination' group (56%) than in the 'sequential monotherapy' (42%, P = 0.002) and the 'stepped-care' group (42%, P = 0.004). CONCLUSIONS: A first line management of hypertension based on a low-dose combination of perindopril and indapamide allows the normalization of blood pressure in significantly more patients than a 'sequential monotherapy' strategy involving atenolol, losartan and amlodipine, and a 'stepped-care' strategy involving valsartan and hydrochlorothiazide. These better blood pressure results were not obtained at the expense of a worsening of tolerability