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https://www.readbyqxmd.com/read/29689099/glycan-modifications-to-the-gp120-immunogens-used-in-the-rv144-vaccine-trial-improve-binding-to-broadly-neutralizing-antibodies
#1
Rachel C Doran, Gwen P Tatsuno, Sara M O'Rourke, Bin Yu, David L Alexander, Kathryn A Mesa, Phillip W Berman
To date, the RV144 HIV vaccine trial has been the only study to show that immunization can confer protection from HIV infection. While encouraging, the modest 31.2% (P = 0.04) efficacy achieved in this study left significant room for improvement, and created an incentive to optimize the AIDSVAX B/E vaccine immunogens to increase the level of vaccine efficacy. Since the completion of the RV144 trial, our understanding of the antigenic structure of the HIV envelope protein, gp120, and of the specificity of broadly neutralizing monoclonal antibodies (bN-mAbs) that bind to it, has significantly improved...
2018: PloS One
https://www.readbyqxmd.com/read/29683765/modeling-cumulative-overall-prevention-efficacy-for-the-vrc01-phase-2b-efficacy-trials
#2
Yunda Huang, Shelly Karuna, Lindsay N Carpp, Daniel Reeves, Amarendra Pegu, Kelly Seaton, Kenneth Mayer, Joshua Schiffer, John Mascola, Peter B Gilbert
The Antibody Mediated Prevention trials are assessing whether intravenously-administered VRC01 (10 mg/kg or 30 mg/kg vs placebo) can prevent HIV infection. In a modeling exercise, we used two models to predict the overall prevention efficacy (PE) of each VRC01 dose in preventing HIV infection. For the first per-exposure PE model, parameters were estimated from studies where nonhuman primates (NHPs) were administered high-dose intra-rectal simian-human immunodeficiency virus challenge two days post-VRC01 infusion at various dosages ("NHP model")...
April 23, 2018: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29669274/superinfection-drives-hiv-neutralizing-antibody-responses-from-several-b-cell-lineages-that-contribute-to-a-polyclonal-repertoire
#3
Katherine L Williams, Bingjie Wang, Dana Arenz, James A Williams, Adam S Dingens, Valerie Cortez, Cassandra A Simonich, Stephanie Rainwater, Dara A Lehman, Kelly K Lee, Julie Overbaugh
Eliciting broad and potent HIV-specific neutralizing antibody responses represents the holy grail of HIV vaccine efforts. Data from singly infected individuals with broad and potent plasma neutralizing activity targeting one epitope have guided our understanding of how these responses develop. However, far less is known about responses developed by superinfected individuals who acquire two distinct HIV strains. Here, we isolated HIV-specific mAbs from a superinfected individual with a broad plasma response...
April 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/29610143/characterization-of-the-antigenic-heterogeneity-of-lipoarabinomannan-the-major-surface-glycolipid-of-mycobacterium-tuberculosis-and-complexity-of-antibody-specificities-toward-this-antigen
#4
Alok Choudhary, Deendayal Patel, William Honnen, Zhong Lai, Raja Sekhar Prattipati, Ruixiang Blake Zheng, Ying-Chao Hsueh, Maria Laura Gennaro, Alfred Lardizabal, Blanca I Restrepo, Moncerrato Garcia-Viveros, Maju Joe, Yu Bai, Ke Shen, Kamar Sahloul, John S Spencer, Delphi Chatterjee, Tobias Broger, Todd L Lowary, Abraham Pinter
Lipoarabinomannan (LAM), the major antigenic glycolipid of Mycobacterium tuberculosis , is an important immunodiagnostic target for detecting tuberculosis (TB) infection in HIV-1-coinfected patients, and is believed to mediate a number of functions that promote infection and disease development. To probe the human humoral response against LAM during TB infection, several novel LAM-specific human mAbs were molecularly cloned from memory B cells isolated from infected patients and grown in vitro. The fine epitope specificities of these Abs, along with those of a panel of previously described murine and phage-derived LAM-specific mAbs, were mapped using binding assays against LAM Ags from several mycobacterial species and a panel of synthetic glycans and glycoconjugates that represented diverse carbohydrate structures present in LAM...
April 2, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29555345/rapid-response-to-an-emerging-infectious-disease-lessons-learned-from-development-of-a-synthetic-dna-vaccine-targeting-zika-virus
#5
Sagar B Kudchodkar, Hyeree Choi, Emma L Reuschel, Rianne Esquivel, Jackie Jin-Ah Kwon, Moonsup Jeong, Joel N Maslow, Charles C Reed, Scott White, J Joseph Kim, Gary P Kobinger, Pablo Tebas, David B Weiner, Kar Muthumani
Vaccines are considered one of the greatest advances in modern medicine. The global burden of numerous infectious diseases has been significantly reduced, and in some cases, effectively eradicated through the deployment of specific vaccines. However, efforts to develop effective vaccines against infectious pathogens such as influenza, HIV, dengue virus (DENV), chikungunya virus (CHIKV), Ebola virus, and Zika virus (ZIKV) have proven challenging. Zika virus is a mosquito-vectored flavivirus responsible for periodic outbreaks of disease in Africa, Southeast Asia, and the Pacific Islands dating back over 50 years...
March 16, 2018: Microbes and Infection
https://www.readbyqxmd.com/read/29528942/neutralization-sensitivity-of-a-novel-hiv-1-crf01_ae-panel-of-infectious-molecular-clones
#6
Agnes-Laurence Chenine, Melanie Merbah, Lindsay Wieczorek, Sebastian Molnar, Brendan Mann, Jenica Lee, Anne Marie O'Sullivan, Meera Bose, Eric Sanders-Buell, Gustavo H Kijak, Carolina Herrera, Robert McLinden, Robert J O'Connell, Nelson L Michael, Merlin L Robb, Jerome H Kim, Victoria R Polonis, Sodsai Tovanabutra
BACKGROUND: HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE derived reagents are essential. Here we present a panel of 14 HIV-1 infectious molecular clones (IMC) identified from different stages of infection, and characterization of their neutralization sensitivity using two standard assays. METHODS: One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1...
March 8, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/29515029/fine-epitope-signature-of-antibody-neutralization-breadth-at-the-hiv-1-envelope-cd4-binding-site
#7
Hao D Cheng, Sebastian K Grimm, Morgan Sa Gilman, Luc Christian Gwom, Devin Sok, Christopher Sundling, Gina Donofrio, Gunilla B Karlsson Hedestam, Mattia Bonsignori, Barton F Haynes, Timothy P Lahey, Isaac Maro, C Fordham von Reyn, Miroslaw K Gorny, Susan Zolla-Pazner, Bruce D Walker, Galit Alter, Dennis R Burton, Merlin L Robb, Shelly J Krebs, Michael S Seaman, Chris Bailey-Kellogg, Margaret E Ackerman
Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth...
March 8, 2018: JCI Insight
https://www.readbyqxmd.com/read/29514914/reduced-cell-associated-dna-and-improved-viral-control-in-macaques-following-passive-transfer-of-a-single-anti-v2-monoclonal-antibody-and-repeated-shiv-challenges
#8
Ann J Hessell, Mariya B Shapiro, Rebecca Powell, Delphine C Malherbe, Sean P McBurney, Shilpi Pandey, Tracy Cheever, William F Sutton, Christoph Kahl, Byung Park, Susan Zolla-Pazner, Nancy L Haigwood
A high level of V1V2-specific IgG antibodies in vaccinees' sera was the only independent variable that correlated with a reduced risk of HIV acquisition in the RV144 clinical trial. In contrast, IgG avidity, antibody neutralization, and antibody-dependent cellular cytotoxicity each failed as independent correlates of infection. Extended analyses of RV144 samples demonstrated antiviral activity of V1V2-specific vaccine-induced antibodies. V2-specific antibodies have also been associated with protection from SIV, and the V2i-specific subset of human monoclonal antibodies (mAbs), while poor neutralizers, mediate Fc-dependent antiviral functions in vitro The objective of this study was to determine the protective efficacy of a V2i-specific human mAb 830A against mucosal SHIV challenge...
March 7, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29512823/variable-domain-n-linked-glycosylation-and-negative-surface-charge-are-key-features-of-monoclonal-acpa-implications-for-b-cell-selection
#9
Katy A Lloyd, Johanna Steen, Khaled Amara, Philip J Titcombe, Lena Israelsson, Susanna L Lundström, Diana Zhou, Roman A Zubarev, Evan Reed, Luca Piccoli, Cem Gabay, Antonio Lanzavecchia, Dominique Baeten, Karin Lundberg, Daniel L Mueller, Lars Klareskog, Vivianne Malmström, Caroline Grönwall
Autoreactive B cells have a central role in the pathogenesis of rheumatoid arthritis (RA), and recent findings have proposed that anti-citrullinated protein autoantibodies (ACPA) may be directly pathogenic. Herein, we demonstrate the frequency of variable-region glycosylation in single-cell cloned mAbs. A total of 14 ACPA mAbs were evaluated for predicted N-linked glycosylation motifs in silico, and compared to 452 highly-mutated mAbs from RA patients and controls. Variable region N-linked motifs (N-X-S/T) were strikingly prevalent within ACPA (100%) compared to somatically hypermutated (SHM) RA bone marrow plasma cells (21%), and synovial plasma cells from seropositive (39%) and seronegative RA (7%)...
March 7, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29508618/hydrolysis-kinetic-study-of-aebsf-a-protease-inhibitor-used-during-cell-culture-processing-of-the-hiv-1-broadly-neutralizing-antibody-cap256-vrc25-26
#10
Jesse L Huang, Attila Nagy, Vera B Ivleva, Daniel Blackstock, Frank Arnold, Cindy X Cai
One approach to mitigate product clipping during HIV mAb CAP256-VRC26.25 cell-culture development is the addition of the protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF) to the cell-culture media. AEBSF can undergo hydrolysis to form an inactive compound, 4-(2-aminoethyl) benzenesulfonic acid. Using mass-spectrometry detection, a kinetic profile of AEBSF hydrolysis was generated for conditions simulating those of cell culture at pH 7.0 and 37 °C. It was found that increasing the pH or the temperature could accelerate AEBSF hydrolysis...
April 3, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29478152/the-role-of-integrin-%C3%AE-4-%C3%AE-7-in-hiv-pathogenesis-and-treatment
#11
REVIEW
James Arthos, Claudia Cicala, Fatima Nawaz, Siddappa N Byrareddy, Francois Villinger, Philip J Santangelo, Aftab A Ansari, Anthony S Fauci
PURPOSE OF REVIEW: Acute HIV infection is characterized by high-level viral replication throughout the body's lymphoid system, particularly in gut-associated lymphoid tissues resulting in damage to structural components of gut tissue. This damage is irreversible and believed to contribute to the development of immune deficiencies. Antiretroviral therapy (ART) does not restore gut structure and function. Studies in macaques point to an alternative treatment strategy that may ameliorate gut damage...
April 2018: Current HIV/AIDS Reports
https://www.readbyqxmd.com/read/29364886/safety-and-pharmacokinetics-of-the-fc-modified-hiv-1-human-monoclonal-antibody-vrc01ls-a-phase-1-open-label-clinical-trial-in-healthy-adults
#12
Martin R Gaudinski, Emily E Coates, Katherine V Houser, Grace L Chen, Galina Yamshchikov, Jamie G Saunders, LaSonji A Holman, Ingelise Gordon, Sarah Plummer, Cynthia S Hendel, Michelle Conan-Cibotti, Margarita Gomez Lorenzo, Sandra Sitar, Kevin Carlton, Carolyn Laurencot, Robert T Bailer, Sandeep Narpala, Adrian B McDermott, Aryan M Namboodiri, Janardan P Pandey, Richard M Schwartz, Zonghui Hu, Richard A Koup, Edmund Capparelli, Barney S Graham, John R Mascola, Julie E Ledgerwood
BACKGROUND: VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor. METHODS AND FINDINGS: This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD)...
January 2018: PLoS Medicine
https://www.readbyqxmd.com/read/29362132/hla-class-i-antigen-processing-machinery-apm-component-expression-and-pd-1-pd-l1-pathway-activation-in-hiv-infected-head-and-neck-cancers
#13
Sara I Pai, J Jack Lee, Thomas E Carey, William H Westra, Soldano Ferrone, Charles Moore, Marina B Mosunjac, Dong M Shin, Robert L Ferris
Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified...
February 2018: Oral Oncology
https://www.readbyqxmd.com/read/29346349/early-treatment-of-siv-macaques-with-an-%C3%AE-4-%C3%AE-7-mab-alters-virus-distribution-and-preserves-cd4-t-cells-in-later-stages-of-infection
#14
P J Santangelo, C Cicala, S N Byrareddy, K T Ortiz, D Little, K E Lindsay, S Gumber, J J Hong, K Jelicic, K A Rogers, C Zurla, F Villinger, A A Ansari, A S Fauci, J Arthos
Integrin α4 β7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4 β7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that α4 β7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes...
December 20, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/29343576/increased-epitope-complexity-correlated-with-antibody-affinity-maturation-and-a-novel-binding-mode-revealed-by-structures-of-rabbit-antibodies-against-the-third-variable-loop-v3-of-hiv-1-gp120
#15
Ruimin Pan, Yali Qin, Marisa Banasik, William Lees, Adrian J Shepherd, Michael W Cho, Xiang-Peng Kong
The V3 loop of HIV-1 gp120 is an immunodominant region targeted by neutralizing antibodies (nAbs). Despite limited breadth, better characterization of the structural details of the interactions between these nAbs and their target epitopes would enhance our understanding of the mechanism of neutralization and facilitate designing better immunogens to induce nAbs with greater breadth. Recently, we isolated two anti-V3 neutralizing monoclonal antibodies (mAbs), 10A3 and 10A37, from a rabbit immunized with gp120 of the M group consensus sequence...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29321320/hiv-1-specific-iga-monoclonal-antibodies-from-an-hiv-1-vaccinee-mediate-galactosylceramide-blocking-and-phagocytosis
#16
Saintedym Wills, Kwan-Ki Hwang, Pinghuang Liu, S Moses Dennison, Matthew Zirui Tay, Xiaoying Shen, Justin Pollara, Judith T Lucas, Robert Parks, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jaranit Kaewkungwal, Rasmi Thomas, Jerome H Kim, Nelson L Michael, Merlin L Robb, Mike McRaven, David C Montefiori, Thomas J Hope, Hua-Xin Liao, M Anthony Moody, Guido Ferrari, Barton F Haynes, S Munir Alam, Mattia Bonsignori, Georgia D Tomaras
Vaccine-elicited humoral immune responses comprise an array of antibody forms and specificities, with only a fraction contributing to protective host immunity. Elucidation of antibody effector functions responsible for protective immunity against human immunodeficiency virus type 1 (HIV-1) acquisition is a major goal for the HIV-1 vaccine field. Immunoglobulin A (IgA) is an important part of the host defense against pathogens; however, little is known about the role of vaccine-elicited IgA and its capacity to mediate antiviral functions...
April 1, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29282882/recent-progress-in-immune-based-interventions-to-prevent-hiv-1-transmission-to-children
#17
Yegor Voronin, Ilesh Jani, Barney S Graham, Coleen K Cunningham, Lynne M Mofenson, Philippa M Musoke, Sallie R Permar, Gabriella Scarlatti
Globally, 150,000 new paediatric human immunodeficiency virus type 1 (HIV-1) infections occurred in 2015. There remain complex challenges to the global elimination of paediatric HIV-1 infection. Thus, for the global community to achieve elimination of new paediatric HIV-1 infections, innovative approaches need to be explored. Immune-based approaches to prevention of mother-to-child transmission (MTCT) may help fill some of the remaining gaps and provide new opportunities to achieve an AIDS-free generation. Immune-based interventions to prevent MTCT of HIV-1 may include paediatric HIV vaccines and passive immunization approaches...
December 2017: Journal of the International AIDS Society
https://www.readbyqxmd.com/read/29281723/human-immunodeficiency-virus-type-1-hiv-1-evades-antibody-dependent-phagocytosis
#18
Johannes S Gach, Margaux Bouzin, Marcus P Wong, Veronika Chromikova, Andrea Gorlani, Kuan-Ting Yu, Brijesh Sharma, Enrico Gratton, Donald N Forthal
Fc gamma receptor (FcyR)-mediated antibody functions play a crucial role in preventing HIV infection. One such function, antibody-dependent phagocytosis (ADP), is thought to be involved in controlling other viral infections, but its role in HIV infection is unknown. We measured the ability of HIV-specific polyclonal and monoclonal antibodies (mAbs) to mediate the internalization of HIV-1 virions and HIV-1-decorated cells by phagocytes. To measure ADP of virions, we primarily used a green-fluorescent protein-expressing molecular clone of HIV-1JRFL, an R5, clinical isolate, in combination with polyclonal HIVIG or mAbs known to capture and/or neutralize HIV-1...
December 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29230203/ibalizumab-targeting-cd4-receptors-an-emerging-molecule-in-hiv-therapy
#19
REVIEW
Simona A Iacob, Diana G Iacob
The HIV infection is responsible for the most devastating global pandemic of the last century. More than 39 million people have died of HIV/AIDS since 1981. The development of the antiretroviral (ARV) treatment begins with the discovery of zidovudine a nucleoside reverse transcriptase inhibitor. This breakthrough was followed by other ARV drug classes and representatives. Presently, HIV treatment employs 27 ARV representatives belonging to five different classes. Despite the proven benefits of ARV treatment and its long-term control of the HIV infection, there is an increasing concern about the numerous adverse effects and resistance to current ARV drugs...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29176985/mucosal-iga-responses-damaged-in-established-hiv-infection-yet-effective-weapon-against-hiv-transmission
#20
REVIEW
Viraj Kulkarni, Ruth M Ruprecht
HIV infection not only destroys CD4+ T cells but also inflicts serious damage to the B-cell compartment, such as lymphadenopathy, destruction of normal B-cell follicle architecture, polyclonal hypergammaglobulinemia, increased apoptosis of B cells, and irreversible loss of memory B-cell responses with advanced HIV disease. Subepithelial B cells and plasma cells are also affected, which results in loss of mucosal IgG and IgA antibodies. This leaves the mucosal barrier vulnerable to bacterial translocation. The ensuing immune activation in mucosal tissues adds fuel to the fire of local HIV replication...
2017: Frontiers in Immunology
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