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Broadly neutralizing antibodies

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https://www.readbyqxmd.com/read/28446665/dense-array-of-spikes-on-hiv-1-virion-particles
#1
Armando Stano, Daniel P Leaman, Arthur S Kim, Lei Zhang, Ludovic Autin, Jidnyasa Ingale, Syna K Gift, Jared Truong, Richard T Wyatt, Arthur J Olson, Michael B Zwick
HIV-1 is rare among viruses for having a low number of envelope glycoprotein (Env) spikes per virion, i.e. ∼7-14. This exceptional feature has been associated with avoidance of humoral immunity, i.e. B cell activation and antibody neutralization. Virus-like particles (VLPs) with increased density of Env are being pursued for vaccine development; however these typically require protein engineering that alters Env structure. Here, we used instead a strategy that targets the producer cell. We employed fluorescence activated cell sorting (FACS) to sort for cells that are recognized by trimer crossreactive broadly neutralizing antibody (bnAb) and not by non-neutralizing antibodies...
April 26, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28446609/glycosylation-of-the-core-of-the-hiv-1-envelope-subunit-protein-gp120-is-not-required-for-native-trimer-formation-or-viral-infectivity
#2
Ujjwal Rathore, Piyali Saha, Sannula Kesavardhana, Aditya Arun Kumar, Rohini Datta, Sivasankar Devanarayanan, Raksha Das, John R Mascola, Raghavan Varadarajan
The gp120 subunit of HIV-1 envelope (Env) protein is heavily glycosylated at approximately 25 glycosylation sites, of which ~7-8 are located in the V1/V2 and V3 variable loops and the others in the remaining core gp120 region. Glycans partially shield Env from recognition by the host immune system and also are believed to be indispensable for proper folding of gp120 and for viral infectivity. Previous attempts to alter glycosylation sites in Env typically involved mutating the glycosylated asparagine residues to structurally similar glutamines or to alanines...
April 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28445718/the-hiv-1-glycan-shield-strategically-placed-kinks-in-the-armor-improve-antigen-design
#3
Christina Beatrice Karsten, Galit Alter
Dense glycosylation on the HIV-1 envelope glycoprotein hampers the induction of broadly neutralizing antibodies against HIV-1. Zhou et al. remove key glycans to unmask sites of vulnerability and enable the induction of neutralizing antibodies.
April 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28436427/broad-and-potent-cross-clade-neutralizing-antibodies-with-multiple-specificities-in-the-plasma-of-hiv-1-subtype-c-infected-individuals
#4
Narayanaiah Cheedarla, K Lucia Precilla, Hemalatha Babu, K K Vidya Vijayan, Manickam Ashokkumar, Padmapriyadarsini Chandrasekaran, Nandagopal Kailasam, Jagadish Chandrabose Sundaramurthi, Soumya Swaminathan, Viswanath Buddolla, S Kalyanaraman Vaniambadi, V D Ramanathan, Luke Elizabeth Hanna
Broadly Cross clade Neutralizing (BCN) antibodies are recognized as potential therapeutic tools and leads for the design of a vaccine that can protect human beings against various clades of Human Immunodeficiency Virus (HIV). In the present study, we screened plasma of 88 HIV-1 infected ART naïve individuals for their neutralization potential using a standard panel of 18 pseudoviruses belonging to different subtypes and different levels of neutralization. We identified 12 samples with good breadth of neutralization (neutralized >90% of the viruses)...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28435154/broadly-neutralizing-antibodies-suppress-post-transcytosis-hiv-1-infectivity
#5
V Lorin, M Malbec, C Eden, T Bruel, F Porrot, M S Seaman, O Schwartz, H Mouquet
No abstract text is available yet for this article.
May 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28429756/a-non-canonical-binding-interface-in-the-crystal-structure-of-hiv-1-gp120-core-in-complex-with-cd4
#6
Liang-Wei Duan, Hui Zhang, Meng-Ting Zhao, Ji-Xue Sun, Wen-Li Chen, Jian-Ping Lin, Xin-Qi Liu
Numerous crystal structures of HIV gp120 have been reported, alone or with receptor CD4 and cognate antibodies; however, no sole gp120/CD4 complex without stabilization by an antibody is available. Here, we report a crystal structure of the gp120/CD4 complex without the aid of an antibody from HIV-1 CRF07_BC, a strain circulating in China. Interestingly, in addition to the canonical binding surface, a second interacting interface was identified. A mutagenesis study on critical residues revealed that the stability of this interface is important for the efficiency of Env-mediated membrane fusion...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28427948/comprehensive-characterization-of-humoral-correlates-of-human-immunodeficiency-virus-1-superinfection-acquisition-in-high-risk-kenyan-women
#7
Keshet Ronen, Adam S Dingens, Susan M Graham, Walter Jaoko, Kishor Mandaliya, R Scott McClelland, Julie Overbaugh
HIV-1 superinfection, in which an infected individual acquires a second HIV-1 infection from a different partner, is one of the only settings in which HIV acquisition occurs in the context of a pre-existing immune response to natural HIV infection. There is evidence that initial infection provides some protection from superinfection, particularly after 6months of initial infection, when development of broad immunity occurs. Comparison of the immune response of superinfected individuals at the time of superinfection acquisition to that of individuals who remain singly infected despite continued exposure can shed light on immune correlates of HIV acquisition to inform prophylactic vaccine design...
April 2017: EBioMedicine
https://www.readbyqxmd.com/read/28424227/onc201-demonstrates-anti-tumor-effects-in-both-triple-negative-and-non-triple-negative-breast-cancers-through-trail-dependent-and-trail-independent-mechanisms
#8
Marie D Ralff, Christina L B Kline, Ozan C Küçükkase, Jessica Wagner, Bora Lim, David T Dicker, Varun V Prabhu, Wolfgang Oster, Wafik S El-Deiry
Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13)--. A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2...
April 19, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28423342/a-broadly-neutralizing-antibody-targets-the-dynamic-hiv-envelope-trimer-apex-via-a-long-rigidified-and-anionic-%C3%AE-hairpin-structure
#9
Jeong Hyun Lee, Raiees Andrabi, Ching-Yao Su, Anila Yasmeen, Jean-Philippe Julien, Leopold Kong, Nicholas C Wu, Ryan McBride, Devin Sok, Matthias Pauthner, Christopher A Cottrell, Travis Nieusma, Claudia Blattner, James C Paulson, Per Johan Klasse, Ian A Wilson, Dennis R Burton, Andrew B Ward
Broadly neutralizing antibodies (bnAbs) to HIV delineate vaccine targets and are prophylactic and therapeutic agents. Some of the most potent bnAbs target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer. Using cryo-electron microscopy, we solved the atomic structure of an apex bnAb, PGT145, in complex with Env. We showed that the long anionic HCDR3 of PGT145 penetrated between glycans at the trimer 3-fold axis, to contact peptide residues from all three Env protomers, and thus explains its highly trimer-specific nature...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28422793/engineering-antibody-like-inhibitors-to-prevent-and-treat-hiv-1-infection
#10
Matthew R Gardner, Michael Farzan
PURPOSE OF REVIEW: Here we discuss recently developed HIV-1 entry inhibitors that can target multiple epitopes on the HIV-1 envelope glycoprotein (Env), with an emphasis on eCD4-Ig. Some of these inhibitors are more potent and broader than any single antibody characterized to date. We also discuss the use of recombinant adeno-associated virus (rAAV) vectors as a platform for long-term expression of these inhibitors. RECENT FINDINGS: Much of the exterior of HIV-1 Env can be targeted by broadly neutralizing antibodies (bNAbs)...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422792/progress-in-hiv-1-antibody-research-using-humanized-mice
#11
Henning Gruell, Florian Klein
PURPOSE OF REVIEW: Recent discoveries of highly potent broadly HIV-1 neutralizing antibodies provide new opportunities to successfully prevent, treat, and potentially cure HIV-1 infection. To test their activity in vivo, humanized mice have been shown to be a powerful model and were used to investigate antibody-mediated prevention and therapy approaches. In this review, we will summarize recent findings in humanized mice that have informed on the potential use of broadly neutralizing antibodies targeting HIV-1 in humans...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422790/particle-based-delivery-of-the-hiv-envelope-protein
#12
Benedikt Asbach, Ralf Wagner
PURPOSE OF REVIEW: A major focus in HIV vaccine research is the development of suitable antigens that elicit broadly neutralizing antibody responses targeting HIV's envelope protein (Env). Delivery of Env in a repetitive manner on particle-based carriers allows higher avidity interactions and is therefore expected to efficiently engage B cells, thus leading to affinity maturation that results in superior antibody responses characterized by improved breadth, potency, and durability. This review summarizes current work that is evaluating diverse types of such particulate carriers for Env delivery...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422789/antigp41-membrane-proximal-external-region-antibodies-and-the-art-of-using-the-membrane-for-neutralization
#13
Nichole Cerutti, Juan Luis Loredo-Varela, Christophe Caillat, Winfried Weissenhorn
PURPOSE OF REVIEW: We summarize the latest research on the progress to understand the neutralizing epitopes present within the membrane proximal external region (MPER) of the HIV-1 fusion protein subunit gp41. RECENT FINDINGS: The HIV-1 fusion protein subunit gp41 contains a highly conserved sequence that is essential for membrane fusion and targeted by broadly neutralizing antibodies such as 2F5, 4E10, Z13e1, and 10E8. These antibodies recognize a linear gp41 epitope with high affinity, but require additional hydrophobic sequences present in their heavy chain CDR3 for neutralization...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422788/stabilized-hiv-1-envelope-glycoprotein-trimers-for-vaccine-use
#14
Max Medina-Ramírez, Rogier W Sanders, Quentin J Sattentau
PURPOSE OF REVIEW: To provide an update on the latest developments in the field of HIV-1 antibody-based soluble envelope glycoprotein (Env) trimer design for vaccine use. RECENT FINDINGS: The development of soluble native-like HIV-1 Env trimer immunogens has moved the field of antibody-based vaccine design forward dramatically over the past few years with refinement of various stabilizing approaches. However, despite this progress, significant challenges remain...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422787/how-hiv-1-entry-mechanism-and-broadly-neutralizing-antibodies-guide-structure-based-vaccine-design
#15
Marie Pancera, Anita Changela, Peter D Kwong
PURPOSE OF REVIEW: An HIV-1 vaccine that elicits broadly neutralizing antibodies (bNAbs) remains to be developed. Here, we review how knowledge of bNAbs and HIV-1 entry mechanism is guiding the structure-based design of vaccine immunogens and immunization regimens. RECENT FINDINGS: Isolation of bNAbs from HIV-1-infected donors has led to an unprecedented understanding of the sites of vulnerability that these antibodies target on the HIV-1 envelope (Env) as well as of the immunological pathways that these antibody lineages follow to develop broad and potent neutralization...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422784/b-cell-abnormalities-and-impact-on-antibody-response-in-hiv-infection
#16
Alessandra Noto, Giuseppe Pantaleo
PURPOSE OF REVIEW: The purpose of the present review is to provide an update on the current development in the field of broadly neutralizing antibodies (bNabs) and their potential use in the prevention and therapeutic settings, and an evaluation of the B-cell abnormalities that may impair antibody responses in HIV infection. RECENT FINDINGS: Major advances have been achieved in the characterization of bNabs directed against different vulnerable regions of HIV Envelope (Env)...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28422783/lessons-learned-from-humoral-responses-of-hiv-patients
#17
Laura E McCoy, Áine McKnight
PURPOSE OF REVIEW: Since 2009 many broadly neutralizing antibodies against HIV have been identified, yet there is still no vaccine capable of inducing such antibodies in humans. This review considers the early observations of HIV sera neutralization in light of more recent studies and highlights areas for future research. RECENT FINDINGS: Large clinical cohort studies using standardized neutralization assays and pseudoviruses derived from primary isolates have shown that 10-30% of HIV infections result in some level of serum neutralization breadth...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28416548/pharmacokinetics-and-preliminary-safety-of-pod-intravaginal-rings-delivering-the-monoclonal-antibody-vrc01-n-for-hiv-prophylaxis-in-a-macaque-model
#18
Chunxia Zhao, Manjula Gunawardana, Francois Villinger, Marc M Baum, Mariana Remedios-Chan, Thomas R Moench, Larry Zeitlin, Kevin J Whaley, Ognian Bohorov, Thomas J Smith, Deborah J Anderson, John A Moss
The broadly neutralizing antibody (bNAb) VRC01, capable of neutralizing 91% of known HIV-1 isolates in vitro, is a promising candidate microbicide for preventing sexual HIV infection when administered topically to the vagina; however, accessibility to antibody-based prophylactic treatment by target populations in sub-Saharan Africa and other under-developed regions may be limited by the high cost and limited manufacturing capacity of conventionally produced antibodies. Intravaginal rings of the pod design (pod-IVRs) delivering Nicotiana-manufactured VRC01-N over a range of release rates have been developed...
April 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28414420/systematic-synthesis-and-binding-study-of-hiv-v3-glycopeptides-reveal-the-fine-epitopes-of-several-broadly-neutralizing-antibodies
#19
Jared Orwenyo, Hui Cai, John Giddens, Mohammed N Amin, Christian Toonstra, Lai-Xi Wang
A class of new glycan-reactive broadly neutralizing antibodies represented by PGT121, 10-1074 and PGT128 has recently been discovered that target specific N-glycans and peptide region around the V3 domain. However, the glycan specificity and fine epitopes of these bNAbs remain to be further defined. We report here a systematic chemoenzymatic synthesis of homogeneous V3 glycopeptides derived from HIV-1 JR-FL strain carrying defined N-glycans at N332, N301 and N295 sites. Antibody binding studies revealed that both the nature and site of glycosylation in the context of the V3 domain were critical for high-affinity binding...
April 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28413045/effector-mechanisms-of-humoral-immunity-to-porcine-reproductive-and-respiratory-syndrome-virus
#20
REVIEW
Michael C Rahe, Michael P Murtaugh
Porcine reproductive and respiratory syndrome virus (PRRSV) continues to afflict swine nearly 30 years after it was first discovered as the causative agent of "mystery swine disease". Immunological tools of vaccination and exposure to virulent viruses have not succeeded in achieving control and prevention of PRRSV. Humoral immunity, mediated by antibodies, is a hallmark of anti-viral immunity, but little is known about the effector mechanisms of humoral immunity against PRRSV. It is essential to understand the immunological significance of antibody functions, including recently described broadly neutralizing antibodies and potential non-neutralizing activities, in the immune response to PRRSV...
April 2017: Veterinary Immunology and Immunopathology
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