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mAb hiv

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
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
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
Matthew Costa, Justin Pollara, Regina Whitney Edwards, Michael Seaman, Miroslaw K Gorny, David 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' infection and, therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that a moderate protection is possible, which may correlate with ADCC activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, DP6-001, a polyvalent Env DNA prime-protein boost formulation, could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities...
September 14, 2016: Journal of Virology
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
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
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
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
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
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
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
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
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
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
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
Ann J Hessell, Sean McBurney, Shilpi Pandey, William Sutton, Lily Liu, Liuzhe Li, Maxim Totrov, Susan Zolla-Pazner, Nancy L Haigwood, Miroslaw K Gorny
RV144 vaccinees with low HIV-1 Envelope-specific IgA antibodies (Abs) also had Abs directed to the hypervariable region 3 (V3) that inversely correlated with infection risk. Thus, anti-V3 HIV-1 Abs may contribute to protection from HIV-1 infection. The V3 region contains two dominant clusters of epitopes; one is preferentially recognized by mAbs encoded by VH5-51 and VL lambda genes, while the second one is recognized by mAbs encoded by other VH genes. We designed a study in rhesus macaques to induce anti-V3 Abs specific to each of these two dominant clusters of V3 epitopes to test whether the usage of the VH5-51 gene results in different characteristics of antibodies...
May 23, 2016: Vaccine
Yi Ma, Chao Ni, Emmanuel E Dzakah, Haiying Wang, Keren Kang, Shixing Tang, Jihua Wang, Jufang Wang
Human immunodeficiency virus type 1 (HIV-1) p24 protein is the most abundant viral protein of HIV-1. This protein is secreted in blood serum at high levels during the early stages of HIV-1 infection, making it a biomarker for early diagnosis. In this study, a colloidal gold immunochromatographic assay (GICA) was established for detecting p24 protein using mouse monoclonal antibodies (mAbs). The HIV-1 p24 protein was expressed in E. coli strain BL21 and the purified protein was used to immunize mice. Stable hybridoma cell lines secreting anti-p24 monoclonal antibodies were obtained after ELISA screening and subcloning by limiting dilution...
2016: BioMed Research International
Rosemarie D Mason, Hugh C Welles, Cameron Adams, Bimal K Chakrabarti, Jason Gorman, Tongqing Zhou, Richard Nguyen, Sijy O'Dell, Sabrina Lusvarghi, Carole A Bewley, Hui Li, George M Shaw, Zizhang Sheng, Lawrence Shapiro, Richard Wyatt, Peter D Kwong, John R Mascola, Mario Roederer
The simian immunodeficiency virus (SIV) challenge model of lentiviral infection is often used as a model to human immunodeficiency virus type 1 (HIV-1) for studying vaccine mediated and immune correlates of protection. However, knowledge of the structure of the SIV envelope (Env) glycoprotein is limited, as is knowledge of binding specificity, function and potential efficacy of SIV antibody responses. In this study we describe the use of a competitive probe binding sort strategy as well as scaffolded probes for targeted isolation of SIV Env-specific monoclonal antibodies (mAbs)...
April 2016: PLoS Pathogens
William D Tolbert, Neelakshi Gohain, Maxime Veillette, Jean-Philippe Chapleau, Chiara Orlandi, Maria L Visciano, Maryam Ebadi, Anthony L DeVico, Timothy R Fouts, Andrés Finzi, George K Lewis, Marzena Pazgier
Evidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond...
May 3, 2016: Structure
Harold Oliva, Rodrigo Pacheco, José M Martinez-Navio, Marta Rodríguez-García, Mar Naranjo-Gómez, Núria Climent, Carolina Prado, Cristina Gil, Montserrat Plana, Felipe García, José M Miró, Rafael Franco, Francesc E Borras, Naveenan Navaratnam, José M Gatell, Teresa Gallart
APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T cells are highly permissive for HIV-1 replication, whereas resting CD4(+) T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory. We investigated whether these differences could be related to a differential A3G expression and/or subcellular distribution. We found that A3G mRNA and protein expression is very low in resting CD4(+) T cells and immature DCs, but increases strongly following T-cell activation and DC maturation...
August 2016: Immunology and Cell Biology
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