Drug-Associated Changes in Amino Acid Residues in Gag p2, p7\u3csup\u3eNC\u3c/sup\u3e, and p6\u3csup\u3eGag\u3c/sup\u3e/p6\u3csup\u3ePol\u3c/sup\u3e in Human Immunodeficiency Virus Type 1 (HIV-1) Display a Dominant Effect on Replicative Fitness and Drug Response

Regions of HIV-1 gag between p2 and p6Gag/p6Pol, in addition to protease (PR), develop genetic diversity in HIV-1 infected individuals who fail to suppress virus replication by combination protease inhibitor (PI) therapy. To elucidate functional consequences for viral replication and PI susceptibility by changes in Gag that evolve in vivo during PI therapy, a panel of recombinant viruses was constructed. Residues in Gag p2/p7NC cleavage site and p7NC, combined with residues in the flap of PR, defined novel fitness determinants that restored replicative capacity to the posttherapy virus. Multiple determinants in Gag have a dominant effect on PR phenotype and increase susceptibility to inhibitors of drug-resistant or drug-sensitive PR genes. Gag determinants of drug sensitivity and replication alter the fitness landscape of the virus, and viral replicative capacity can be independent of drug sensitivity. The functional linkage between Gag and PR provides targets for novel therapeutics to inhibit drug-resistant viruses

Drug-associated changes in amino acid residues in Gag p2, p7NC, and p6Gag/p6Pol in human immunodeficiency virus type 1 (HIV-1) display a dominant effect on replicative fitness and drug response

AbstractRegions of HIV-1 gag between p2 and p6Gag/p6Pol, in addition to protease (PR), develop genetic diversity in HIV-1 infected individuals who fail to suppress virus replication by combination protease inhibitor (PI) therapy. To elucidate functional consequences for viral replication and PI susceptibility by changes in Gag that evolve in vivo during PI therapy, a panel of recombinant viruses was constructed. Residues in Gag p2/p7NC cleavage site and p7NC, combined with residues in the flap of PR, defined novel fitness determinants that restored replicative capacity to the posttherapy virus. Multiple determinants in Gag have a dominant effect on PR phenotype and increase susceptibility to inhibitors of drug-resistant or drug-sensitive PR genes. Gag determinants of drug sensitivity and replication alter the fitness landscape of the virus, and viral replicative capacity can be independent of drug sensitivity. The functional linkage between Gag and PR provides targets for novel therapeutics to inhibit drug-resistant viruses

Expression, purification and preliminary X-ray crystallographic studies of the human immunodeficiency virus 1 subtype C protease

Crystals of the human immunodeficiency virus 1 subtype C protease complexed with indinavir and nelfinavir have been grown in the monoclinic space group P21 and shown to diffract X-rays to 2.3 Å resolution

Left main coronary artery compression in precapillary pulmonary hypertension

Abstract Pulmonary hypertension (PH) is a progressive and invalidating condition despite available therapy. Addressing complications such as left main coronary artery compression (LMCo) due to the dilated pulmonary artery (PA) may improve symptoms and survival. Nevertheless, clear recommendations are lacking. The aim of this study is to analyze the prevalence, characteristics, predictive factors and impact of LMCo in a heterogenous precapillary PH population in a single referral center. Two hundred sixty‐five adults with various etiologies of precapillary PH at catheterization were reviewed. Coronary angiography (CA) was performed for LMCo suspicion. Revascularization was performed in selected cases. Outcomes were assessed at a mean follow‐up of 3.9 years. LMCo was suspected in 125 patients and confirmed in 39 (31.2%), of whom 21 (16.8%) had 50%–90% stenoses. Nine revascularizations were performed, with clinical improvement. The only periprocedural complication was a stent migration. LMCo was associated with PH etiology (p 0.003), occuring more frequently in congenital heart disease‐associated PH (61.5% of all LMCo cases, 66.6% of LMCo ≥ 50%). Predictors of LMCo ≥50% were PA ≥ 37.5 mm (Sn 81%, Sp 74%) and PA‐to‐aorta ≥1.24 (Sn 81%, Sp 69%), with increased discrimination when considering RV end‐diastolic area. LMCo ≥ 50% without revascularization presented clinical deterioration and worse survival (p 0.019). This analysis of a heterogeneous pre‐capillary PH population provides LMCo prevalence estimation, predictive factors (PA size, PA‐to‐aorta, RV end‐diastolic area and PH etiology) and long‐term impact. While LMCo impact on survival is inconclusive, untreated LMCo ≥ 50% has worse prognosis. LMCo revascularization may be performed safely and with good outcomes

Left atrial dysfunction as a correlate of heart failure symptoms in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) represents a generalized myopathic process affecting both ventricular and atrial myocardium. We aimed to assess left atrial (LA) function by two-dimensional speckle tracking echocardiography and its relation with left ventricular (LV) function and clinical status in patients with HCM. METHODS: We prospectively enrolled 37 consecutive patients with HCM and 37 normal subjects with similar age and gender distribution. Longitudinal LV strain (epsilon) and LA epsilon and strain rate (Sr) parameters (systolic, early diastolic, and late diastolic during atrial contraction) were assessed. RESULTS: Peak LAepsilon and LA Sr parameters were significantly lower in patients compared with controls (P </= .001 for all). In patients, all LA function parameters correlated with LVepsilon (P < .003 for all). Indexed LA volume, LA function parameters, and mitral regurgitation degree were the main correlates of New York Heart Association class; late diastolic strain rate during atrial contraction was the only independent predictor of symptomatic status. CONCLUSION: In patients with HCM, LA function is significantly reduced and related to LV dysfunction. Moreover, LA booster pump function emerged as an independent correlate of heart failure symptoms in this setting

Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes

The crystal structure of the unbound form of HIV-1 subtype A protease has been determined to 1.7 Å resolution. A detailed structural analysis and comparison of the unbound subtype A, B and C protease structures is presented. The results showed that although no inhibitor is present in the active site, the subtype A protease has flaps in the closed position