Isolation and structure of broad SIV-neutralizing antibodies reveal a proximal helical MPER epitope recognized by a rhesus multi-donor class.

The membrane-proximal external region (MPER) of the HIV-1 envelope is a target for broadly neutralizing antibodies (bnAbs), and vaccine-elicited MPER-directed antibodies have recently been reported from a human clinical trial. In this study, we sought to identify MPER-directed nAbs in simian immunodeficiency virus (SIV)-infected rhesus macaques. We isolated four lineages of SIV MPER-directed nAbs from two SIV-infected macaques.

Long trimer-immunization interval and appropriate adjuvant reduce immune responses to the soluble HIV-1-envelope trimer base.

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth.

Soluble prefusion-closed HIV-envelope trimers with glycan-covered bases.

Soluble HIV-1-envelope (Env) trimers elicit immune responses that target their solvent-exposed protein bases, the result of removing these trimers from their native membrane-bound context. To assess whether glycosylation could limit these base responses, we introduced sequons encoding potential -linked glycosylation sites (PNGSs) into base-proximal regions. Expression and antigenic analyses indicated trimers bearing six-introduced PNGSs to have reduced base recognition.

Broad and ultra-potent cross-clade neutralization of HIV-1 by a vaccine-induced CD4 binding site bovine antibody.

Human immunodeficiency virus type 1 (HIV-1) vaccination of cows has elicited broadly neutralizing antibodies (bNAbs). In this study, monoclonal antibodies (mAbs) are isolated from a clade A (KNH1144 and BG505) vaccinated cow using a heterologous clade B antigen (AD8). CD4 binding site (CD4bs) bNAb (MEL-1872) is more potent than a majority of CD4bs bNAbs isolated so far.

Enhancement of Antibody-Dependent Cellular Cytotoxicity and Phagocytosis in Anti-HIV-1 Human-Bovine Chimeric Broadly Neutralizing Antibodies.

No prophylactic vaccine has provided robust protection against human immunodeficiency virus type 1 (HIV-1). Vaccine-induced broadly neutralizing antibodies (bNAbs) have not been achieved in humans and most animals; however, cows vaccinated with HIV-1 envelope trimers produce bNAbs with unusually long third heavy complementarity-determining regions (CDRH3s). Alongside neutralization, Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), may be critical for bNAb antiviral activity.

Fusion peptide priming reduces immune responses to HIV-1 envelope trimer base.

Soluble "SOSIP"-stabilized envelope (Env) trimers are promising HIV-vaccine immunogens. However, they induce high-titer responses against the glycan-free trimer base, which is occluded on native virions. To delineate the effect on base responses of priming with immunogens targeting the fusion peptide (FP) site of vulnerability, here, we quantify the prevalence of trimer-base antibody responses in 49 non-human primates immunized with various SOSIP-stabilized Env trimers and FP-carrier conjugates.

Immunogenicity of HIV-1-Based Virus-Like Particles with Increased Incorporation and Stability of Membrane-Bound Env.

An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice.

HIV-1-based Virus-like Particles that Morphologically Resemble Mature, Infectious HIV-1 Virions.

A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-structured, virion-associated Env to elicit bNAbs, and also stimulate T cell responses. Here, we optimize our DNA vaccine plasmids as VLP expression vectors for efficient Env incorporation and budding.

Trimeric gp120-specific bovine monoclonal antibodies require cysteine and aromatic residues in CDRH3 for high affinity binding to HIV Env.

We isolated HIV-1 Envelope (Env)-specific memory B cells from a cow that had developed high titer polyclonal immunoglobulin G (IgG) with broad neutralizing activity after a long duration vaccination with HIV-1 Env gp140 trimers. We cloned the bovine IgG matched heavy (H) and light (L) chain variable (V) genes from these memory B cells and constructed IgG monoclonal antibodies (mAbs) with either a human constant (C)-region/bovine V-region chimeric or fully bovine C and V regions. Among 42 selected Ig+ memory B cells, two mAbs (6A and 8C) showed high affinity binding to gp140 Env.

Repeated Vaccination of Cows with HIV Env gp140 during Subsequent Pregnancies Elicits and Sustains an Enduring Strong Env-Binding and Neutralising Antibody Response.

An important feature of a potential vaccine against HIV is the production of broadly neutralising antibodies (BrNAbs) capable of potentially blocking infectivity of a diverse array of HIV strains. BrNAbs naturally arise in some HIV infected individuals after several years of infection and their serum IgG can neutralise various HIV strains across different subtypes. We previously showed that vaccination of cows with HIV gp140 AD8 trimers resulted in a high titre of serum IgG against HIV envelope (Env) that had strong BrNAb activity.

Endogenous Murine BST-2/Tetherin Is Not a Major Restriction Factor of Influenza A Virus Infection.

BST-2 (tetherin, CD317, HM1.24) restricts virus growth by tethering enveloped viruses to the cell surface. The role of BST-2 during influenza A virus infection (IAV) is controversial.

Breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity: relevance to global HIV vaccine design.

Objective: The objective of this study is to determine the breadth of HIV-1 Env-specific antibody-dependent cellular cytotoxicity (ADCC) in HIV controllers and HIV progressors with a view to design globally relevant HIV vaccines.

Design: The breadth of ADCC towards four major HIV-1 Env subtypes was measured in vitro for 11 HIV controllers and 11 HIV progressors.

Methods: Plasma from 11 HIV controllers (including long-term slow progressors, viremic controllers, elite controller and posttreatment controller) and 11 HIV progressors, mostly infected with HIV-1 subtype B, was analysed for ADCC responses.