HIV Specific B Cell Response in Patients With Broadly Neutralizing Serum Activity

Antibodies to conserved epitopes on the HIV surface protein gp140 can protect against infection in non-human primates, suggesting that vaccines that elicit such antibodies would be protective. Some HIV infected individuals develop high titers of broadly neutralizing IgG antibodies in their serum, but until recently very little was known about the specificity and activity of these antibodies. To characterize the broadly neutralizing memory antibody responses to HIV we cloned 1078 antibodies from HIV envelope binding memory B cells from eight HIV infected patients with broadly neutralizing antibodies. We found that in these patients, the B cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity antibodies to the gp120 variable loops, the CD4 binding site, the co-receptor binding site, to a new neutralizing epitope that is in the same region of gp120 as the CD4 binding site and to gp41. In four patients highly potent broadly neutralizing antibody clones directed to the CD4 binding site were isolated. Despite extensive hypermutation, these broadly neutralizing CD4bs antibodies shared a consensus sequence of 68 IgH chain amino acids and arose independently from two related IgH genes. Thus, the IgG memory B cell compartment in the selected group of patients with broad serum activity to HIV is comprised of multiple clonal responses. Neutralizing activity is directed against several epitopes on gp120 with some closely related CD4 binding site directed antibody clones showing highly potent neutralizing activity. For the first time, this study has attempted to systematically describe on a monoclonal level the composition of broadly neutralizing serum activity against HIV. The techniques and antibodies presented in this work are transforming our understanding of possible targets and routes for HIV vaccine strategies and provide powerful tools for possible HIV treatment approaches

Towards Optimal Free Trade Agreement Utilization through Deep Learning Techniques

In recent years, deep learning based methods achieved new state of the art in various domains such as image recognition, speech recognition and natural language processing. However, in the context of tax and customs, the amount of existing applications of artificial intelligence and more specifically deep learning is limited. In this paper, we investigate the potentials of deep learning techniques to improve the Free Trade Agreement (FTA) utilization of trade transactions. We show that supervised learning models can be trained to decide on the basis of transaction characteristics such as import country, export country, product type, etc. whether FTA can be utilized. We apply a specific architecture with multiple embeddings to efficiently capture the dynamics of tabular data. The experiments were evaluated on real-world data generated by Enterprise Resource Planning (ERP) systems of an international chemical and consumer goods company

Human immunodeficiency virus neutralizing antibodies and methods of use thereof [APPLICATION]

The invention provides broadly neutralizing antibodies directed to epitopes of Human Immunodeficiency Virus, or HIV. The invention further provides compositions containing HIV antibodies used for prophylaxis, and methods for diagnosis and treatment of HIV infection

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env1, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans

Human immunodeficiency virus neutralizing antibodies and methods of use thereof [APPLICATION]

The invention provides broadly neutralizing antibodies directed to epitopes of Human Immunodeficiency Virus, or HIV. The invention further provides compositions containing HIV antibodies used for prophylaxis, and methods for diagnosis and treatment of HIV infection

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env1, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans

Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody

Efforts to design an effective antibody-based vaccine against HIV-1 would benefit from understanding how germ-line B-cell receptors (BCRs) recognize the HIV-1 gp120/gp41 envelope spike. Potent VRC01-like (PVL) HIV-1 antibodies derived from the VH1-2*02 germ-line allele target the conserved CD4 binding site on gp120. A bottleneck for design of immunogens capable of eliciting PVL antibodies is that VH1-2*02 germ-line BCR interactions with gp120 are uncharacterized. Here, we report the structure of a VH1-2*02 germ-line antibody alone and a germ-line heavy-chain/mature light-chain chimeric antibody complexed with HIV-1 gp120. VH1-2*02 residues make extensive contacts with the gp120 outer domain, including all PVL signature and CD4 mimicry interactions, but not critical CDRH3 contacts with the gp120 inner domain and bridging sheet that are responsible for the improved potency of NIH45-46 over closely related clonal variants, such as VRC01. Our results provide insight into initial recognition of HIV-1 by VH1-2*02 germ-line BCRs and may facilitate the design of immunogens tailored to engage and stimulate broad and potent CD4 binding site antibodies

Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design

Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity–determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46^(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46–gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies

Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies

Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions