HIV capsid is a tractable target for small molecule therapeutic intervention.

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.

Effect of Functional Impact Training on Body Composition, Bone Mineral Density, and Strength in Breast Cancer Survivors.

PURPOSE: The purpose of this study was to examine the effects of 24 wk of functional impact training (FIT) that consisted of resistance and high-impact exercises in comparison with yin yoga on body composition, bone mineral density (BMD), blood biomarkers for bone metabolism, and strength in breast cancer survivors (BCS). METHODS: Forty-four BCS (60.3 ± 8.3 yr) were randomly assigned to the FIT or yin yoga group. Body composition and BMD were measured via dual energy x-ray absorptiometry. Blood biomarkers for bone metabolism were analyzed via enzyme-linked immunosorbent assays. Upper and lower body strength was assessed using a one-repetition maximum chest press and isokinetic knee extension/flexion using the Biodex System 3, respectively. Participants completed 45-min FIT or yin yoga sessions twice weekly for 24 wk. Changes in dependent variables over time were analyzed using repeated-measures ANOVA. Significance was accepted at P ≤ 0.05. RESULTS: There were no group-time effects for body composition, BMD, or blood biomarkers. Main effects were observed for left femoral neck (0.883 ± 0.138 to 0.870 ± 0.131 g·cm) and left forearm (0.465 ± 0.078 to 0.457 ± 0.069 g·cm) BMD. The FIT group improved upper body strength (73.2 ± 18.1 to 83.2 ± 22.3 kg), whereas the yin yoga group did not (59.8 ± 14.8 to 59.3 ± 15.6 kg). Main time effects were observed for peak isokinetic knee extension and flexion at all speeds with an average improvement of 13.2% and 16.2%, respectively. CONCLUSION: Both FIT and yin yoga may be beneficial exercise modes for improving lower body strength, although only FIT improved upper body strength. Additional research is needed to examine the effectiveness of FIT programs of longer duration and/or higher intensity on body composition and BMD in BCS.

The effect of cold ambient temperature and preceding active warm-up on lactate kinetics in female cyclists and triathletes.

The aim of this study was to evaluate the effect of cold ambient temperature on lactate kinetics with and without a preceding warm-up in female cyclists/triathletes. Seven female cyclists/triathletes participated in this study. The randomized, crossover study included 3 experimental visits that comprised the following conditions: (i) thermoneutral temperature (20 °C; NEU); (ii) cold temperature (0 °C) with no active warm-up (CNWU); and (iii) cold temperature (0 °C) with 25-min active warm-up (CWU). During each condition, participants performed a lactate threshold (LT) test followed by a time to exhaustion trial at 120% of the participant's peak power output (PPO) as determined during prior peak oxygen consumption testing. Power output at LT with CNWU was 10.2% ± 2.6% greater than with NEU, and the effect was considered very likely small (effect size (ES) = 0.59, 95%-99% likelihood). Power output at LT with CNWU was 4.2% ± 5.4% greater than with CWU; however, the effect was likely trivial (ES = 0.25, 75%-95% likelihood). At LT, there were no significant differences between interventions groups in oxygen consumption, blood lactate concentration, heart rate, or rating of perceived exertion. Time to exhaustion at 120% at PPO was 11% longer with CNWU than with CWU (ES = 0.62, respectively), and this effect was likely small. These findings suggest that power output at LT was higher in CNWU compared with NEU. Additionally, time to exhaustion at 120% of PPO was higher in CNWU compared with CWU and no different than NEU; these differences likely result in a small improvement in performance with CNWU versus CWU and NEU.

Colony-forming assays reveal enhanced suppression of hepatitis C virus replication using combinations of direct-acting antivirals.

The current standard of care for patients infected with hepatitis C virus (HCV) is not effective universally and is associated with severe side effects. Direct-acting antiviral molecules have potential to transform treatment of HCV-infected individuals but emergence of drug-resistant virus will be problematic. It is anticipated that, to limit the emergence of drug-resistant virus, future HCV therapies must consist of multiple direct-acting antivirals. In the present study, cell culture-based colony-forming assays were used to demonstrate enhanced suppression of HCV RNA replication following simultaneous treatment of HCV replicon-containing cells with two direct-acting antivirals. Specifically, combinations of NS5Ai and Filibuvir (small molecule inhibitors of HCV-encoded NS5A and NS5B proteins respectively) were able to suppress colony formation fully at concentrations that individually they could not. HCV replicon RNA isolated from colonies that emerged following treatment with suboptimal concentrations of NS5Ai were found to encode resistance substitutions in the NS5A gene, which rendered them insensitive to subsequent high doses of NS5Ai. Furthermore, both NS5Ai and Filibuvir were effective at suppressing colony formation in combination with BILN 2061, an inhibitor of HCV-encoded NS3. Collectively, these data underscore the increased inhibitory capacity of direct-acting antivirals to suppress HCV RNA replication when present in combination.