Mutations of Glu560 within HIV-1 Envelope Glycoprotein N-terminal heptad repeat region contribute to resistance to peptide inhibitors of virus entry.

BACKGROUND: Peptides corresponding to N- and C-terminal heptad repeat regions (HR1 and HR2, respectively) of gp41 can inhibit HIV-1 infection in a dominant negative manner by interfering with refolding of the viral HR1 and HR2 to form a six-helix bundle (6HB) that induces fusion between viral and host cell membranes. Previously, we found that HIV-1 acquired the mutations of Glu560 (E560) in HR1 of envelope (Env) to escape peptide inhibitors. The present study aimed to elucidate the critical role of position 560 in the virus entry and potential resistance mechanisms. RESULTS: The Glu560Lys/Asp/Gly (E560K/D/G) mutations in HR1 of gp41 that are selected under the pressure of N- and C-peptide inhibitors modified its molecular interactions with HR2 to change 6HB stability and peptide inhibitor binding. E560K mutation increased 6HB thermostability and resulted in resistance to N peptide inhibitors, but E560G or E560D as compensatory mutations destabilized the 6HB to reduce inhibitor binding and resulted in increased resistance to C peptide inhibitor, T20. Significantly, the neutralizing activities of all mutants to soluble CD4 and broadly neutralizing antibodies targeting membrane proximal external region, 2F5 and 4E10 were improved, indicating the mutations of E560 could regulate Env conformations through cross interactions with gp120 or gp41. The molecular modeling analysis of E560K/D/G mutants suggested that position 560 might interact with the residues within two potentially flexible topological layer 1 and layer 2 in the gp120 inner domain to apparently affect the CD4 utilization. The E560K/D/G mutations changed its interactions with Gln650 (Q650) in HR2 to contribute to the resistance of peptide inhibitors. CONCLUSIONS: These findings identify the contributions of mutations of E560K/D/G in the highly conserved gp41 and highlight Env's high degree of plasticity for virus entry and inhibitor design.

[Evaluation of alveolar bone defect in chronic periodontitis by cone-beam computed tomography].

OBJECTIVE: To evaluate the morphological characteristics of alveolar bone defects of the patients with chronic periodontitis using cone-beam CT (CBCT). METHODS: Sixty patients with chronic periodontitis were included in this study. CBCT was used to scan the alveolar bone and NNT software to measure the alveolar bone defects and bone loss types in different regions. RESULTS: Seventy-five percent (45/60) of the alveolar bone defect was the generalized type, 25% (15/60) was the localized type. In incisor and canine area, the defect of the mandibular alveolar bone was more severe than in the same sites of maxilla. There was less bone loss in the premolar area of mandible than in the same site of maxilla. In the mesial and buccal sites of mandibular molars and in the lingual site of maxillary molars, the most severe alveolar bone loss was found. CONCLUSIONS: The obvious alveolar bone defect areas in chronic periodontitis were the palatal side of maxillary molars and the lingual side of mandibular incisors. CBCT can clearly demonstrate the degree of alveolar bone defects in different regions of chronic periodontitis.