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Hiv and broadly neutralizing antibody

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
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
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
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
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
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
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
Heather A Prentice, Hailin Lu, Matthew A Price, Anatoli Kamali, Etienne Karita, Shabir Lakhi, Eduard J Sanders, Omu Anzala, Susan Allen, Paul A Goepfert, Eric Hunter, Jill Gilmour, Jianming Tang
: In individuals with HIV-1 infection, depletion of CD4(+) T-cells is often accompanied by a malfunction of CD8(+) T-cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well-documented, the same does not apply to CD8 counts. Here, we examined CD8 counts in a cohort of 497 Africans with primary HIV-1 infection and monthly to quarterly follow-up visits for up to three years in the absence of antiretroviral therapy. Statistical models revealed that i) CD8 counts were relatively steady in the 3-36 months period of infection and similar between men and women; ii) neither geography nor heterogeneity in HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort (P >0...
September 14, 2016: Journal of Virology
Joseph G Jardine, Devin Sok, Jean-Philippe Julien, Bryan Briney, Anita Sarkar, Chi-Hui Liang, Erin M Scherer, Carole J Henry Dunand, Yumiko Adachi, Devan Diwanji, Jessica Hsueh, Meaghan Jones, Oleksandr Kalyuzhniy, Michael Kubitz, Skye Spencer, Matthias Pauthner, Karen L Saye-Francisco, Fabian Sesterhenn, Patrick C Wilson, Denise A Galloway, Robyn L Stanfield, Ian A Wilson, Dennis R Burton, William R Schief
[This corrects the article DOI: 10.1371/journal.ppat.1005815.].
September 2016: PLoS Pathogens
P J Klasse, Celia C LaBranche, Thomas J Ketas, Gabriel Ozorowski, Albert Cupo, Pavel Pugach, Rajesh P Ringe, Michael Golabek, Marit J van Gils, Miklos Guttman, Kelly K Lee, Ian A Wilson, Salvatore T Butera, Andrew B Ward, David C Montefiori, Rogier W Sanders, John P Moore
We have investigated the immunogenicity in rabbits of native-like, soluble, recombinant SOSIP.664 trimers based on the env genes of four isolates of human immunodeficiency virus type 1 (HIV-1); specifically BG505 (clade A), B41 (clade B), CZA97 (clade C) and DU422 (clade C). The various trimers were delivered either simultaneously (as a mixture of clade A + B trimers) or sequentially over a 73-week period. Autologous, Tier-2 neutralizing antibody (NAb) responses were generated to the clade A and clade B trimers in the bivalent mixture...
September 2016: PLoS Pathogens
Jon M Steichen, Daniel W Kulp, Talar Tokatlian, Amelia Escolano, Pia Dosenovic, Robyn L Stanfield, Laura E McCoy, Gabriel Ozorowski, Xiaozhen Hu, Oleksandr Kalyuzhniy, Bryan Briney, Torben Schiffner, Fernando Garces, Natalia T Freund, Alexander D Gitlin, Sergey Menis, Erik Georgeson, Michael Kubitz, Yumiko Adachi, Meaghan Jones, Andrew A Mutafyan, Dong Soo Yun, Christian T Mayer, Andrew B Ward, Dennis R Burton, Ian A Wilson, Darrell J Irvine, Michel C Nussenzweig, William R Schief
Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline-reverted precursors of PGT121-class supersite bnAbs...
September 20, 2016: Immunity
Harry B Gristick, Lotta von Boehmer, Anthony P West, Michael Schamber, Anna Gazumyan, Jovana Golijanin, Michael S Seaman, Gerd Fätkenheuer, Florian Klein, Michel C Nussenzweig, Pamela J Bjorkman
HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-Å- and 3.9-Å-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs...
October 2016: Nature Structural & Molecular Biology
Todd Bradley, Ashley Trama, Nancy Tumba, Elin Gray, Xiaozhi Lu, Navid Madani, Fatemeh Jahanbakhsh, Amanda Eaton, Shi-Mao Xia, Robert Parks, Krissey E Lloyd, Laura L Sutherland, Richard M Scearce, Cindy M Bowman, Susan Barnett, Salim S Abdool-Karim, Scott D Boyd, Bruno Melillo, Amos B Smith, Joseph Sodroski, Thomas B Kepler, S Munir Alam, Feng Gao, Mattia Bonsignori, Hua-Xin Liao, M Anthony Moody, David Montefiori, Sampa Santra, Lynn Morris, Barton F Haynes
Most HIV-1 vaccines elicit neutralizing antibodies that are active against highly sensitive (tier-1) viruses or rare cases of vaccine-matched neutralization-resistant (tier-2) viruses, but no vaccine has induced antibodies that can broadly neutralize heterologous tier-2 viruses. In this study, we isolated antibodies from an HIV-1-infected individual that targeted the gp41 membrane-proximal external region (MPER) that may have selected single-residue changes in viral variants in the MPER that resulted in neutralization sensitivity to antibodies targeting distal epitopes on the HIV-1 Env...
August 31, 2016: EBioMedicine
Ming Tian, Cheng Cheng, Xuejun Chen, Hongying Duan, Hwei-Ling Cheng, Mai Dao, Zizhang Sheng, Michael Kimble, Lingshu Wang, Sherry Lin, Stephen D Schmidt, Zhou Du, M Gordon Joyce, Yiwei Chen, Brandon J DeKosky, Yimin Chen, Erica Normandin, Elizabeth Cantor, Rita E Chen, Nicole A Doria-Rose, Yi Zhang, Wei Shi, Wing-Pui Kong, Misook Choe, Amy R Henry, Farida Laboune, Ivelin S Georgiev, Pei-Yi Huang, Suvi Jain, Andrew T McGuire, Eric Georgeson, Sergey Menis, Daniel C Douek, William R Schief, Leonidas Stamatatos, Peter D Kwong, Lawrence Shapiro, Barton F Haynes, John R Mascola, Frederick W Alt
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors...
September 8, 2016: Cell
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