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Broadly neutralizing antibodies

Boopathy Ramakrishnan, Karthik Viswanathan, Kannan Tharakaraman, Vlado Dančík, Rahul Raman, Gregory J Babcock, Zachary Shriver, Ram Sasisekharan
Broadly neutralizing monoclonal antibodies (bNAbs) for viral infections, such as HIV, respiratory syncytial virus (RSV), and influenza, are increasingly entering clinical development. For influenza, most neutralizing antibodies target influenza virus hemagglutinin. These bNAbs represent an emerging, promising modality for treatment and prophylaxis of influenza due to their multiple mechanisms of antiviral action and generally safe profile. Preclinical work in other viral diseases, such as dengue, has demonstrated the potential for antibody-based therapies to enhance viral uptake, leading to enhanced viremia and worsening of disease...
October 14, 2016: Trends in Microbiology
Freek Cox, Ted Kwaks, Boerries Brandenburg, Martin H Koldijk, Vincent Klaren, Bastiaan Smal, Hans J W M Korse, Eric Geelen, Lisanne Tettero, David Zuijdgeest, Esther J M Stoop, Eirikur Saeland, Ronald Vogels, Robert H E Friesen, Wouter Koudstaal, Jaap Goudsmit
Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the in vivo protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies...
2016: Frontiers in Immunology
Ming Sun, Yue Li, Huiwen Zheng, Yiming Shao
The recent discoveries of broadly potent neutralizing human monoclonal antibodies represent a new generation of antiretrovirals for the treatment and prophylaxis. Antibodies are generally considered more effective and safer and have been proved to provide passive protection against mucosal challenge in humanized mice and macaques. Several neutralizing Abs could protect animals against HIV-1 but are not effective when used in an established infected model for therapy. In order to overcome the limitation of antiviral activities, multiple antibody-engineering technologies have been explored to generate "the better" neutralizing antibodies against HIV-1 since bNAbs attack viral entry by various mechanisms...
2016: Frontiers in Immunology
Mahmoud Mohammad Yaseen, Mohammad Mahmoud Yaseen, Mohammad Ali Alqudah
Although available antiretroviral therapy (ART) has changed human immunodeficiency virus (HIV)-1 infection to a non-fatal chronic disease, the economic burden of lifelong therapy, severe adverse ART effects, daily ART adherence, and emergence of ART-resistant HIV-1 mutants require prospecting for alternative therapeutic modalities. Indeed, a growing body of evidence suggests that broadly neutralizing anti-HIV-1 antibodies (BNAbs) may offer one such feasible alternative. To evaluate their therapeutic potential in established HIV-1 infection, we sought to address recent advances in pre-clinical and clinical investigations in this area of HIV-1 research...
October 14, 2016: International Reviews of Immunology
Ting Zhang, Hongyang Liu, Xue Chen, Zhirong Wang, Shuo Wang, Chunfeng Qu, Jingzhi Zhang, Xuemei Xu
Numerous types of human papillomaviruses (HPVs) have been identified, and the global burden of diseases associated with HPV infection is remarkable, especially in developing regions. Thus a low-cost broad-spectrum prophylactic vaccine is urgently needed. The N-terminal amino acid 17-36 of HPV 16 L2 protein is confirmed to be a major cross-neutralizing epitope (RG-1 epitope). Monomeric proteins containing RG-1 epitopes and scaffold proteins, such as bacterial thioredoxin or modified IgG1 Fc fragment and L2 epitope fusion protein, induced cross-neutralizing antibodies, arousing the possibility of the development of low-cost monomeric vaccine in bacterial expression system...
October 8, 2016: Vaccine
Jianhui Tian, Cesar A López, Cynthia A Derdeyn, Morris S Jones, Abraham Pinter, Bette Korber, S Gnanakaran
Heavy glycosylation of the envelope (Env) surface subunit, gp120, is a key adaptation of HIV-1; however, the precise effects of glycosylation on the folding, conformation and dynamics of this protein are poorly understood. Here we explore the patterns of HIV-1 Env gp120 glycosylation, and particularly the enrichment in glycosylation sites proximal to the disulfide linkages at the base of the surface-exposed variable domains. To dissect the influence of glycans on the conformation these regions, we focused on an antigenic peptide fragment from a disulfide bridge-bounded region spanning the V1 and V2 hyper-variable domains of HIV-1 gp120...
October 2016: PLoS Computational Biology
Karen P Coss, Snezana Vasiljevic, Laura K Pritchard, Stefanie A Krumm, Molly Glaze, Sharon Madzorera, Penny L Moore, Max Crispin, Katie J Doores
: The HIV envelope (Env) is extensively modified with host-derived N-linked glycans. The high density of glycosylation on the viral spike limits enzymatic processing resulting in numerous under-processed oligomannose-type glycans. This extensive glycosylation not only shields conserved regions of the protein from the immune system but also act as targets for HIV broadly neutralizing antibodies (bnAbs). In response to the host immune system, the HIV glycan shield is constantly evolving through mutations affecting both the positions and frequencies of potential N-linked glycans (PNGSs)...
October 5, 2016: Journal of Virology
Xunqing Jiang, Max Totrov, Wei Li, Jared M Sampson, Constance Williams, Hong Lu, Xueling Wu, Shan Lu, Shixia Wang, Susan Zolla-Pazner, Xiang-Peng Kong
: The V1V2 region of HIV-1 gp120 harbors a major vulnerable site targeted by a group of broadly neutralizing mAbs such as PG9 through strand-strand recognition. However, this epitope region is structurally polymorphic, as it can also form a helical conformation recognized by RV144 vaccine-induced mAb CH58. This structural polymorphism is a potential mechanism for masking the V1V2 vulnerable site. Designing immunogens that can induce conformation-specific Ab responses may lead to vaccines targeting this vulnerable site...
October 5, 2016: Journal of Virology
Caitlin E Mullarkey, Mark J Bailey, Diana A Golubeva, Gene S Tan, Raffael Nachbagauer, Wenqian He, Kyle E Novakowski, Dawn M Bowdish, Matthew S Miller, Peter Palese
: Broadly neutralizing antibodies that recognize the conserved hemagglutinin (HA) stalk have emerged as exciting new biotherapeutic tools to combat seasonal and pandemic influenza viruses. Our general understanding of the mechanisms by which stalk-specific antibodies achieve protection is rapidly evolving. It has recently been demonstrated that broadly neutralizing HA stalk-specific IgG antibodies require Fc-Fcγ receptor (FcγR) interactions for optimal protection in vivo Here we examine the neutrophil effector functions induced by stalk-specific antibodies...
October 4, 2016: MBio
Wenqian He, Gene S Tan, Caitlin E Mullarkey, Amanda J Lee, Mannie Man Wai Lam, Florian Krammer, Carole Henry, Patrick C Wilson, Ali A Ashkar, Peter Palese, Matthew S Miller
The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Maximilian Muenchhoff, Emily Adland, Owen Karimanzira, Carol Crowther, Matthew Pace, Anna Csala, Ellen Leitman, Angeline Moonsamy, Callum McGregor, Jacob Hurst, Andreas Groll, Masahiko Mori, Smruti Sinmyee, Christina Thobakgale, Gareth Tudor-Williams, Andrew J Prendergast, Henrik Kloverpris, Julia Roider, Alasdair Leslie, Delane Shingadia, Thea Brits, Samantha Daniels, John Frater, Christian B Willberg, Bruce D Walker, Thumbi Ndung'u, Pieter Jooste, Penny L Moore, Lynn Morris, Philip Goulder
Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy-naïve children aged >5 years maintaining normal-for-age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml)...
September 28, 2016: Science Translational Medicine
Muntasir Alam, Takeo Kuwata, Kazuya Shimura, Masaru Yokoyama, Kristel Paola Ramirez Valdez, Kazuki Tanaka, Yasuhiro Maruta, Shinya Oishi, Nobutaka Fujii, Hironori Sato, Masao Matsuoka, Shuzo Matsushita
BACKGROUND: HIV-1 typically develops resistance to any single antiretroviral agent. Combined anti-retroviral therapy to reduce drug-resistance development is necessary to control HIV-1 infection. Here, to assess the utility of a combination of antibody and fusion inhibitor treatments, we investigated the potency of monoclonal antibodies at neutralizing HIV-1 variants that are resistant to fusion inhibitors. RESULTS: Mutations that confer resistance to four fusion inhibitors, enfuvirtide, C34, SC34, and SC34EK, were introduced into the envelope of HIV-1JR-FL, a CCR5-tropic tier 2 strain...
September 27, 2016: Retrovirology
Peter Rusert, Roger D Kouyos, Claus Kadelka, Hanna Ebner, Merle Schanz, Michael Huber, Dominique L Braun, Nathanael Hozé, Alexandra Scherrer, Carsten Magnus, Jacqueline Weber, Therese Uhr, Valentina Cippa, Christian W Thorball, Herbert Kuster, Matthias Cavassini, Enos Bernasconi, Matthias Hoffmann, Alexandra Calmy, Manuel Battegay, Andri Rauch, Sabine Yerly, Vincent Aubert, Thomas Klimkait, Jürg Böni, Jacques Fellay, Roland R Regoes, Huldrych F Günthard, Alexandra Trkola
Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0...
September 26, 2016: Nature Medicine
Lisa Wasilewski, Stuart Ray, Justin Richard Bailey
A better understanding of natural variation in neutralization resistance and fitness of diverse hepatitis C virus (HCV) envelope (E1E2) variants will be critical to guide rational development of an HCV vaccine. This work has been hindered by inadequate genetic diversity in viral panels and by a lack of standardization of HCV entry assays. Neutralization assays generally use lentiviral pseudoparticles expressing HCV envelope proteins (HCVpp) or chimeric full-length viruses that are replication competent in cell culture (HCVcc)...
September 21, 2016: Journal of General Virology
Marlies M van Haaren, Tom L G M van den Kerkhof, Marit J van Gils
So far, the development of a human immunodeficiency virus (HIV) vaccine has been unsuccessful. However, recent progress in the field of broadly neutralizing antibodies (bNAbs) has reinvigorated the search for an HIV vaccine. bNAbs develop in a minority of HIV infected individuals and passive transfer of these bNAbs to non-human primates provides protection from HIV infection. Studies in a number of HIV infected individuals on bNAb maturation alongside viral evolution and escape have shed light on the features important for bNAb elicitation...
September 20, 2016: Human Vaccines & Immunotherapeutics
Muzamil Ashraf Makhdoomi, Deepti Singh, Ambili Nair Pananghat, Rakesh Lodha, Sushil Kumar Kabra, Kalpana Luthra
Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been extensively tested against pesudoviruses of diverse strains. We generated and characterized HIV-1 primary isolates from antiretroviral naïve infected Indian children, and determined their susceptibility to known NAbs. All the 8 isolates belonged to subtype-C and were R5 tropic. Majority of these viruses were resistant to neutralization by NAbs, suggesting that the bnAbs, known to efficiently neutralize pseudoviruses (adult and pediatric) of different strains, are less effective against pediatric primary isolates...
September 16, 2016: Virology
Jens Bukh
The discovery of hepatitis C virus (HCV) in 1989 permitted basic research to unravel critical components of a complex life cycle for this important human pathogen. HCV is a highly divergent group of viruses classified in 7 major genotypes and a great number of subtypes, and circulating in infected individuals as a continuously evolving quasispecies destined to escape host immune responses and applied antivirals. Despite the inability to culture patient viruses directly in the laboratory, efforts to define the infectious genome of HCV resulted in development of experimental recombinant in vivo and in vitro systems, including replicons and infectious cultures in human hepatoma cell lines...
October 2016: Journal of Hepatology
Zhen-Yong Keck, Yong Wang, Patrick Lau, Garry Lund, Sneha Rangarajan, Catherine Fauvelle, Grant C Liao, Frederick W Holtsberg, Kelly L Warfield, M Javad Aman, Brian G Pierce, Thomas R Fuerst, Justin R Bailey, Thomas F Baumert, Roy A Mariuzza, Norman M Kneteman, Steven K H Foung
: Direct acting antivirals (DAAs) have led to a high cure rate in treated patients with chronic hepatitis C virus (HCV) infection but this still leaves a large number of treatment failures secondary to the emergence of resistance-associated variants (RAVs). To increase the barrier to resistance, a complementary strategy is to employ neutralizing human monoclonal antibodies (HMAbs) to prevent acute infection. However, earlier efforts with the selected antibodies led to RAVs in animal and clinical studies...
September 19, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Terza Brostoff, Patricia A Pesavento, Christopher M Barker, Joan L Kenney, Elizabeth A Dietrich, Nisha K Duggal, Angela M Bosco-Lauth, Aaron C Brault
West Nile virus (WNV) is an important agent of human encephalitis that has quickly become endemic across much of the United States since its identification in North America in 1999. While the majority (∼75%) of infections are subclinical, neurologic disease can occur in a subset of cases, with outcomes including permanent neurologic damage and death. Currently, there are no WNV vaccines approved for use in humans. This study introduces a novel vaccine platform for WNV to reduce viral replication in the central nervous system while maintaining peripheral replication to elicit strong neutralizing antibody titers...
October 17, 2016: Vaccine
Jeffrey T Safrit, Wayne C Koff
PURPOSE OF REVIEW: The purpose is to review recent novel approaches in HIV vaccine research and development being undertaken in the preclinical and early clinical space, as well as related and novel nonvaccine approaches such as genetic delivery of broadly neutralizing antibodies for protection from HIV infection and AIDS. RECENT FINDINGS: We review novel HIV envelope immunogen design, including native trimer and germline targeting approaches as well as genetic delivery of broadly neutralizing antibodies and replicating vector vaccinesSUMMARY: Despite 30+ years of research and development, and billions of dollars spent, a well tolerated and effective HIV vaccine remains a public health priority for any chance of ending the AIDS pandemic...
November 2016: Current Opinion in HIV and AIDS
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