Synthesis and characterization of polynitro-[2.2]paracyclophanes, a novel xylylene polymer, and poly(p-phenylene sulfoxide).

A less closely related polymer, poly(p-phenylene sulfoxide) (PPSX) (18) was synthesized by a novel homogenous oxidation of poly(p-phenylene sulfide) 17 with neat fuming nitric acid, fuming nitric acid in trifluoroacetic acid (TFA), and concentrated nitric acid in TFA. Several model compounds and modified reactions were studied which implicated a nitrogen oxide adduct as a major and required element in the selective oxidation to the polysulfoxide rather than the polysulfone. The intrinsic viscosity of the PPSX polymer was determined to be 0.274. PPSX was successfully fractionated yielding a high molecular weight polymer identified by GPC (Mw = 84,000 and Mn = 30,800). Multiple unitary and binary solvent systems were identified for PPSX, and clear, free-standing, flexible films were cast with plasticizer enhancement. Thermal analysis identified PPSX as an amorphous polymer with a decomposition temperature in air of 334° C and in helium of 342° C. The activation energies of the thermal decomposition of PPSX in air and helium were determined by the Friedman method to be 32 +/- 6 and 31 +/- 3 kcal/mol, respectively. PPSX successfully demonstrated the ability to chelate several metals in experiments intended to explore metal extraction applications.A novel polymer derived from these synthetic routes, poly(2,6-dimethyl- p-xylylene) (21), was synthesized and characterized. This amorphous, soluble polymer had the highest molecular weight of any literature reported xylylene polymer measured by GPC (Mw = 150,500 and Mn = 60,5 10). The polymer 21 exhibited excellent thermal stability in helium and air. The onset of thermal decomposition in air (424° C) was more than 100° C higher than all non-fluorinated xylylene polymers. Excellent quality, freestanding, flexible films of 21 were cast from chloroform.With the goal of better understanding previously documented, structurally related, exothermic decompositions of polynitro-paracyclophanes (polynitroPCP), two novel tetramethyl-tetranitro-[2.2]paracyclophanes and their related polymer were synthesized and characterized: 4,8,12,16-tetramethyl-5,7,13,15-tetranitro[2.2]paracyclophane (45) and 4,8,13,15-tetramethyl-5,7,12,16-tetranitro[2.2]paracyclophane (46), and poly(2,6-dimethyl-3, 5-dinitro-p-xylylene) (20). These compounds and previously synthesized dinitro[2.2]PCP's were characterized by DSC thermal analysis techniques. Compounds 45, 46, and 20 decomposed exothermically at 314, 303, and 281° C, respectively. The exothermic decompositions of the polynitroPCP's are not a product of the strain in the dimer [2.2]PCP members of this class, but rather a feature of the ethano bridge system. The elevation of the decomposition temperatures by 33° C in the non-polymer polynitroPCP's is likely due to an attenuation of intermolecular nitro group interactions caused by intramolecular nitro group orientation restrictions. A smaller 10° C decomposition temperature variation in the dinitro[2.2]PCP's follows a similar trend of likely nitro group orientation restrictions. The severely basic and nucleophilic conditions of the Hofmann elimination also proved incompatible to the synthesis of less methylated polynitroPCP's

The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial

The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01(B) vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01(B)_2 group, N=64) or 3 (F4/AS01(B)_3 group, N=62) doses of F4/AS01(B) or placebo (control group, N=64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4(+) T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01(B)_2 and control group (0.073 log(10)copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01(B)_3 and control group (-0.096 log(10)copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4(+) T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01(B) recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01(B)_2 group: angioedema). F4/AS01(B) induced polyfunctional F4-specific CD4(+) T-cells, but had no significant impact on F4-specific CD8(+) T-cell and anti-F4 antibody levels.F4/AS01(B) had a clinically acceptable safety profile, induced F4-specific CD4(+) T-cell responses, but did not reduce HIV-1 VL, impact CD4(+) T-cells count, delay ART initiation, or prevent HIV-1 related clinical events

Superior Control of HIV-1 Replication by CD8+ T Cells Targeting Conserved Epitopes: Implications for HIV Vaccine Design

<div><p>A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8⁺ T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8⁺ T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8⁺ T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8⁺ T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8⁺ T cells recognizing at least one conserved epitope had 1.4 log₁₀ lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8⁺ T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8⁺ T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8⁺ T cell responses to multiple conserved epitopes of HIV-1.</p></div