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https://www.readbyqxmd.com/read/27913647/diversity-of-antiviral-igg-effector-activities-observed-in-hiv-infected-and-vaccinated-subjects
#1
Yunda Huang, Guido Ferrari, Galit Alter, Donald N Forthal, John C Kappes, George K Lewis, J Christopher Love, Bhavesh Borate, Linda Harris, Kelli Greene, Hongmei Gao, Tran B Phan, Gary Landucci, Brittany A Goods, Karen G Dowell, Hao D Cheng, Chris Bailey-Kellogg, David C Montefiori, Margaret E Ackerman
Diverse Ab effector functions mediated by the Fc domain have been commonly associated with reduced risk of infection in a growing number of nonhuman primate and human clinical studies. This study evaluated the anti-HIV Ab effector activities in polyclonal serum samples from HIV-infected donors, VAX004 vaccine recipients, and healthy HIV-negative subjects using a variety of primary and cell line-based assays, including Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cell-mediated viral inhibition, and Ab-dependent cellular phagocytosis...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27852851/identification-of-human-anti-hiv-gp160-monoclonal-antibodies-that-make-effective-immunotoxins
#2
Seth H Pincus, Kejing Song, Grace A Maresh, Dean H Hamer, Dimiter S Dimitrov, Weizao Chen, Mei-Yun Zhang, Victor F Ghetie, Po-Ying Chan-Hui, James E Robinson, Ellen S Vitetta
: The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fc-mediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities...
November 16, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27815444/an-hiv-1-env-antibody-complex-focuses-antibody-responses-to-conserved-neutralizing-epitopes
#3
Yajing Chen, Richard Wilson, Sijy O'Dell, Javier Guenaga, Yu Feng, Karen Tran, Chi-I Chiang, Heather E Arendt, Joanne DeStefano, John R Mascola, Richard T Wyatt, Yuxing Li
Elicitation of broadly neutralizing Ab (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1-infected individuals. Comparison of the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed mAbs indicates that the latter fail to neutralize primary virus isolates because they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27795412/design-and-in-vivo-characterization-of-immunoconjugates-targeting-hiv-gp160
#4
Seth H Pincus, Kejing Song, Grace A Maresh, Anderson Frank, David Worthylake, Hye-Kyung Chung, Patricia Polacino, Dean H Hamer, Cody P Coyne, Michael G Rosenblum, John W Marks, Gang Chen, Deborah Weiss, Victor Ghetie, Ellen S Vitetta, James E Robinson, Shiu-Lok Hu
: The envelope (Env) glycoprotein of HIV is expressed on the surface of productively-infected cells, and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties including toxins, drugs, or radionuclides are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27788205/a-cinnamon-derived-procyanidin-compound-displays-anti-hiv-1-activity-by-blocking-heparan-sulfate-and-co-receptor-binding-sites-on-gp120-and-reverses-t-cell-exhaustion-via-impeding-tim-3-and-pd-1-upregulation
#5
Bridgette Janine Connell, Sui-Yuan Chang, Ekambaranellore Prakash, Rahima Yousfi, Viswaraman Mohan, Wilfried Posch, Doris Wilflingseder, Christiane Moog, Eiichi N Kodama, Pascal Clayette, Hugues Lortat-Jacob
Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range...
2016: PloS One
https://www.readbyqxmd.com/read/27725635/envelope-specific-antibodies-and-antibody-derived-molecules-for-treating-and-curing-hiv-infection
#6
Guido Ferrari, Barton F Haynes, Scott Koenig, Jeffrey L Nordstrom, David M Margolis, Georgia D Tomaras
HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4(+) T cells and thus limit the spread of progeny virus...
October 7, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27707920/rationally-designed-immunogens-targeting-hiv-1-gp120-v1v2-induce-distinct-conformation-specific-antibody-responses-in-rabbits
#7
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 monoclonal antibodies (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 antibody (Ab) responses may lead to vaccines targeting this vulnerable site...
December 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27667465/-upregulated-pd-1-on-cd8-t-cells-is-positively-correlated-with-activation-of-t-cells-during-hiv-1-infection
#8
Jian Xiao, Xian Liu, Xiaolei Yu, Yuan Dong, Xuqin Wang, Jing Leng, Rongge Yang, Ying Wang
Objective To investigate the expressions of programmed death-1 (PD-1), CD38, human leukocyte antigen DR (HLA-DR) and anligen KI-67(ki67) on CD8(+) T cells, and the correlation between PD-1/PD-L1 pathway and activation, immunodepletion during HIV-1 infection. Methods Peripheral blood mononuclear cells were isolated by density gradient centrifugation from 87 HIV-1 patients and 22 healthy controls. The expression levels of PD-1, CD38, HLA-DR and ki67 on CD8(+)T cells were detected by flow cytometry. Furthermore, we evaluated the production of interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α) in CD8(+) T cells by blocking PD-1/PD-L1 pathway in the presence of PD-L1 mAb...
October 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/27630232/fc-receptor-mediated-activities-of-env-specific-human-monoclonal-antibodies-generated-from-volunteers-receiving-the-dna-prime-protein-boost-hiv-vaccine-dp6-001
#9
Matthew R Costa, Justin Pollara, Regina Whitney Edwards, Michael S Seaman, Miroslaw K Gorny, David C Montefiori, Hua-Xin Liao, Guido Ferrari, Shan Lu, Shixia Wang
: HIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities...
November 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27610570/tailored-immunogens-direct-affinity-maturation-toward-hiv-neutralizing-antibodies
#10
Bryan Briney, Devin Sok, Joseph G Jardine, Daniel W Kulp, Patrick Skog, Sergey Menis, Ronald Jacak, Oleksandr Kalyuzhniy, Natalia de Val, Fabian Sesterhenn, Khoa M Le, Alejandra Ramos, Meaghan Jones, Karen L Saye-Francisco, Tanya R Blane, Skye Spencer, Erik Georgeson, Xiaozhen Hu, Gabriel Ozorowski, Yumiko Adachi, Michael Kubitz, Anita Sarkar, Ian A Wilson, Andrew B Ward, David Nemazee, Dennis R Burton, William R Schief
Induction of broadly neutralizing antibodies (bnAbs) is a primary goal of HIV vaccine development. VRC01-class bnAbs are important vaccine leads because their precursor B cells targeted by an engineered priming immunogen are relatively common among humans. This priming immunogen has demonstrated the ability to initiate a bnAb response in animal models, but recall and maturation toward bnAb development has not been shown. Here, we report the development of boosting immunogens designed to guide the genetic and functional maturation of previously primed VRC01-class precursors...
September 8, 2016: Cell
https://www.readbyqxmd.com/read/27579713/antibody-mediated-internalization-of-infectious-hiv-1-virions-differs-among-antibody-isotypes-and-subclasses
#11
Matthew Zirui Tay, Pinghuang Liu, LaTonya D Williams, Michael D McRaven, Sheetal Sawant, Thaddeus C Gurley, Thomas T Xu, S Moses Dennison, Hua-Xin Liao, Agnès-Laurence Chenine, S Munir Alam, M Anthony Moody, Thomas J Hope, Barton F Haynes, Georgia D Tomaras
Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency...
August 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27576440/hiv-1-clade-c-escapes-broadly-neutralizing-autologous-antibodies-with-n332-glycan-specificity-by-distinct-mechanisms
#12
Suprit Deshpande, Shilpa Patil, Rajesh Kumar, Tandile Hermanus, Kailapuri G Murugavel, Aylur K Srikrishnan, Suniti Solomon, Lynn Morris, Jayanta Bhattacharya
The glycan supersite centered on N332 in the V3 base of the HIV-1 envelope (Env) is a target for broadly neutralizing antibodies (bnAbs) such as PGT121 and PGT128. In this study, we examined the basis of resistance of HIV-1 clade C Envs obtained from broadly cross neutralizing (BCN) plasma of an Indian donor with N332 specificity. Pseudotyped viruses expressing autologous envs were found to be resistant to autologous BCN plasma as well as to PGT121 and PGT128 mAbs despite the majority of Envs containing an intact N332 residue...
2016: Retrovirology
https://www.readbyqxmd.com/read/27512064/epitope-independent-purification-of-native-like-envelope-trimers-from-diverse-hiv-1-isolates
#13
Hans P Verkerke, James A Williams, Miklos Guttman, Cassandra A Simonich, Yu Liang, Modestas Filipavicius, Shiu-Lok Hu, Julie Overbaugh, Kelly K Lee
UNLABELLED: Soluble forms of trimeric HIV-1 envelope glycoprotein (Env) have long been sought as immunogens and as reagents for analysis of Env structure and function. Isolation of trimers that mimic native Env, derived from diverse viruses, however, represents a major challenge. Thus far, the most promising native-like (NL) structures have been obtained by engineering trimer-stabilizing mutations, termed SOSIP, into truncated Env sequences. However, the abundances of NL trimeric conformers vary among Envs, necessitating purification by monoclonal antibodies (MAbs) like PGT145, which target specific epitopes...
October 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27450516/uncommon-structural-motifs-dominate-the-antigen-binding-site-in-human-autoantibodies-reactive-with-basement-membrane-collagen
#14
Mary H Foster, Elizabeth S Buckley, Benny J Chen, Kwan-Ki Hwang, Amy G Clark
Autoantibodies mediate organ destruction in multiple autoimmune diseases, yet their origins in patients remain poorly understood. To probe the genetic origins and structure of disease-associated autoantibodies, we engrafted immunodeficient mice with human CD34+ hematopoietic stem cells and immunized with the non-collagenous-1 (NC1) domain of the alpha3 chain of type IV collagen. This antigen is expressed in lungs and kidneys and is targeted by autoantibodies in anti-glomerular basement membrane (GBM) nephritis and Goodpasture syndrome (GPS), prototypic human organ-specific autoimmune diseases...
August 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27449907/fragments-of-the-v1-v2-domain-of-hiv-1-glycoprotein-120-engineered-for-improved-binding-to-the-broadly-neutralizing-pg9-antibody
#15
Javier F Morales, Bin Yu, Gerardo Perez, Kathryn A Mesa, David L Alexander, Phillip W Berman
The V1/V2 domain of the HIV-1 envelope protein gp120 possesses two important epitopes: a glycan-dependent epitope recognized by the prototypic broadly neutralizing monoclonal antibody (bN-mAb), PG9, as well as an epitope recognized by non-neutralizing antibodies that has been associated with protection from HIV infection in the RV144 HIV vaccine trial. Because both of these epitopes are poorly immunogenic in the context of full length envelope proteins, immunization with properly folded and glycosylated fragments (scaffolds) represents a potential way to enhance the immune response to these specific epitopes...
September 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27368120/a-micro-polyethylene-glycol-precipitation-assay-as-a-relative-solubility-screening-tool-for-monoclonal-antibody-design-and-formulation-development
#16
Vishal M Toprani, Sangeeta B Joshi, Lisa A Kueltzo, Richard M Schwartz, C Russell Middaugh, David B Volkin
Adequate protein solubility is an important prerequisite for development, manufacture, and administration of biotherapeutic drug candidates, especially for high-concentration protein formulations. A previously established method for determining the relative apparent solubility (thermodynamic activity) of proteins using polyethylene glycol (PEG) precipitation is adapted for screening and comparing monoclonal antibody (mAb) candidates where only limited quantities (≤1 mg) are available. This micro-PEG assay is used to evaluate various broadly neutralizing mAb candidates to HIV-1 viral spike (gp120 and gp41 glycoproteins)...
August 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27348748/a-small-molecule-which-competes-with-madcam-1-activates-integrin-%C3%AE-4%C3%AE-7-and-fails-to-prevent-mucosal-transmission-of-shiv-sf162p3
#17
Géraldine Arrode-Brusés, Diana Goode, Kyle Kleinbeck, Jolanta Wilk, Ines Frank, Siddappa Byrareddy, James Arthos, Brooke Grasperge, James Blanchard, Thomas Zydowsky, Agegnehu Gettie, Elena Martinelli
Mucosal HIV-1 transmission is inefficient. However, certain viral and host characteristics may play a role in facilitating HIV acquisition and systemic expansion. Cells expressing high levels of integrin α4β7 have been implicated in favoring the transmission process and the infusion of an anti-α4β7 mAb (RM-Act-1) prior to, and during a repeated low-dose vaginal challenge (RLDC) regimen with SIVmac251 reduced SIV acquisition and protected the gut-associated lymphoid tissues (GALT) in the macaques that acquired SIV...
June 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27315479/engineered-bispecific-antibodies-with-exquisite-hiv-1-neutralizing-activity
#18
Yaoxing Huang, Jian Yu, Anastasia Lanzi, Xin Yao, Chasity D Andrews, Lily Tsai, Mili R Gajjar, Ming Sun, Michael S Seaman, Neal N Padte, David D Ho
While the search for an efficacious HIV-1 vaccine remains elusive, emergence of a new generation of virus-neutralizing monoclonal antibodies (mAbs) has re-ignited the field of passive immunization for HIV-1 prevention. However, the plasticity of HIV-1 demands additional improvements to these mAbs to better ensure their clinical utility. Here, we report engineered bispecific antibodies that are the most potent and broad HIV-neutralizing antibodies to date. One bispecific antibody, 10E8V2.0/iMab, neutralized 118 HIV-1 pseudotyped viruses tested with a mean 50% inhibitory concentration (IC50) of 0...
June 16, 2016: Cell
https://www.readbyqxmd.com/read/27152362/maturational-characteristics-of-hiv-specific-antibodies-in-viremic-individuals
#19
Eric Meffre, Aaron Louie, Jason Bannock, Leo J Y Kim, Jason Ho, Cody C Frear, Lela Kardava, Wei Wang, Clarisa M Buckner, Yimeng Wang, Olivia R Fankuchen, Kathleen R Gittens, Tae-Wook Chun, Yuxing Li, Anthony S Fauci, Susan Moir
Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM)...
2016: JCI Insight
https://www.readbyqxmd.com/read/27128502/regulation-of-gag-and-env-specific-cd8-t-cell-responses-in-art-na%C3%A3-ve-hiv-infected-patients-potential-implications-for-individualized-immunotherapy
#20
Christian Prebensen, Andreas Lind, Anne-Ma Dyrhol-Riise, Dag Kvale
Strategies to develop a functional cure for HIV infection will likely require boosting of effector T cell responses to eliminate reactivated, latently infected cells. We have recently explored an assay for assessing antigen-specific regulation of T cell proliferation, which was related to clinical progression in untreated patients and to vaccine efficacy in two trials of therapeutic Gag-based vaccines. We here expand the same assay to further investigate regulation mediated by various inhibitory pathways. Peripheral blood mononuclear cells from 26 asymptomatic HIV-infected, antiretroviral therapy-naïve patients were stimulated with Gag and Env overlapping peptide panels for 5 days...
2016: PloS One
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