Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes ~98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site-of-vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical Arg/Lys just prior to the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 Env.

The HIV-1-envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a postfusion state. As the sole viral antigen on the HIV-1-virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5-Å resolution for an HIV-1-Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the prefusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Prefusion gp41 encircles N- and C-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry likely involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the prefusion closed spike: we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.

Background 24The COVID-19 pandemic caused by SARS-CoV-2 coronavirus threatens global public 25 health. Currently, neutralizing antibodies (NAbs) versus this virus are expected to 26 correlate with recovery and protection of this disease. However, the characteristics of 27 these antibodies have not been well studied in association with the clinical 28 manifestations in patients. 30 Methods 31Plasma collected from 175 COVID-19 recovered patients with mild symptoms were 32 screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization 33 assay. Spike-binding antibody in plasma were determined by ELISA using RBD, S1, 34 and S2 proteins of SARS-CoV-2. The levels and the time course of SARS-CoV-2-35 specific NAbs and the spike-binding antibodies were monitored at the same time. 36 37 Findings 38 SARS-CoV-2 NAbs were unable to cross-reactive with SARS-CoV virus. SARS-CoV-39 2-specific NAbs were detected in patients from day 10-15 after the onset of the disease 40 and remained thereafter. The titers of NAb among these patients correlated with the 41 spike-binding antibodies targeting S1, RBD, and S2 regions. The titers of NAbs were 42 variable in different patients. Elderly and middle-age patients had significantly higher 43 plasma NAb titers (P<0.0001) and spike-binding antibodies (P=0.0003) than young 44 patients. Notably, among these patients, there were ten patients whose NAb titers were 45 under the detectable level of our assay (ID50: < 40); while in contrast, two patients, 46 showed very high titers of NAb, with ID50 :15989 and 21567 respectively. The NAb 47 titers were positive correlated with plasma CRP levels but negative correlated with the 48 lymphocyte counts of patients at the time of admission, indicating an association 49 between humoral response and cellular immune response.50 51 Interpretation 52The variations of SARS-CoV-2 specific NAbs in recovered COVID-19 patients may 53 raise the concern about the role of NAbs on disease progression. The correlation of 54 NAb titers with age, lymphocyte counts, and blood CRP levels suggested that the 55 interplay between virus and host immune response in coronavirus infections should be 56 further explored for the development of effective vaccine against SARS-CoV-2 virus. 57 Furthermore, titration of NAb is helpful prior to the use of convalescent plasma for 58 prevention or treatment. Sciences 64 65 66 67 All rights reserved. No reuse allowed without permission.