Browsing by Author "Bailer, Robert T."

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Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge.
(American Association for the Advancement of Science., 2017) Julg, Boris.; Tartaglia, Lawrence J.; Keele, Brandon F.; Wagh, Kshitij.; Pegu, Amarendra.; Sok, Devin.; Abbink, Peter.; Schmidt, Stephen D.; Wang, Keyun.; Chen, Xuejun.; Joyce, M. Gordon.; Georgiev, Ivelin S.; Choe, Misook.; Kwong, Peter D.; Doria-Rose, Nicole A.; Le, Khoa.; Louder, Mark K.; Bailer, Robert T.; Moore, Penelope L.; Korber, Bette T. M.; Seaman, Michael S.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Koup, Richard A.; Mascola, John R.; Burton, Dennis R.; Barouch, Dan H.
Abstract available in pdf.
Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization.
(American Association for the Advancement of Science., 2012) Georgiev, Ivelin S.; Doria-Rose, Nicole A.; Zhou, Tongqing.; Do Kwon, Young.; Staupe, Ryan P.; Moquin, Stephanie.; Chuang, Gwo-Yu.; Louder, Mark K.; Schmidt, Stefan.; Altae-Tran, Han R.; Bailer, Robert T.; McKee, Krisha.; Nason, Martha.; O'Dell, Sijy.; Ofek, Gilad.; Pancera, Marie.; Srivatsan, Sanjay.; Shapiro, Lawrence.; Connors, Mark.; Migueles, Stephen A.; Morris, Lynn.; Nishimura, Yoshiaki.; Martin, Malcolm A.; Mascola, John R.; Kwong, Peter D.
Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1–neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined “neutralization fingerprints” for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1–infected donors and a chimeric siman-human immunodeficiency virus–infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection.
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.
(Macmillan Publishers Limited., 2014) Doria-Rose, Nicole A.; Schramm, Chaim A.; Gorman, Jason.; Moore, Penelope L.; Bhiman, Jinal N.; DeKosky, Brandon J.; Ernandes, Michael J.; Georgiev, Ivelin S.; Kim, Helen J.; Pancera, Marie.; Staupe, Ryan P.; Altae-Tran, Han R.; Bailer, Robert T.; Crooks, Ema T.; Druz, Aliaksandr.; Garrett, Nigel Joel.; Hoi, Kam H.; Kong, Rui.; Louder, Mark K.; Longo, Nancy S.; McKee, Krisha.; Nonyane, Molati.; O’Dell, Sijy.; Roark, Ryan S.; Rudicell, Rebecca S.; Schmidt, Stephen D.; Sheward, Daniel J.; Soto, Cinque.; Wibmer, Constantinos Kurt.; Yang, Yongping.; Zhang, Zhenhai.; Mullikin, James C.; Binley, James M.; Sanders, Rogier W.; Wilson, Ian A.; Moore, John P.; Ward, Andrew B.; Georgiou, George.; Williamson, Carolyn.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Kwong, Peter D.; Shapiro, Lawrence.; Mascola, John R.
Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
Identification of broadly neutralizing antibody epitopes in 1 the HIV-1 envelope glycoprotein using evolutionary models.
(Virology Journal, 2013) Lacerda, Miguel.; Moore, Penelope L.; Ngandu, Nobubelo K.; Seaman, Michael.; Gray, Elin Solomonovna.; Murrell, Ben.; Krishnamoorthy, Mohan.; Nonyane, Molati.; Madiga, Maphuti C.; Wibmer, Constantinos Kurt.; Sheward, Daniel J.; Bailer, Robert T.; Gao, Hongmei.; Greene, Kelli M.; Abdool Karim, Salim Safurdeen.; Mascola, John R.; Korber, Bette T. M.; Montefiori, David Charles.; Morris, Lynn.; Williamson, Carolyn.; Seoighe, Cathal.
Background: Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods: We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope. Results: We applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis. Conclusions: Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth.
Mapping polyclonal HIV-1 antibody responses via next-generation neutralization fingerprinting.
(Public Library of Science., 2017) Doria-Rose, Nicole A.; Altae-Tran, Han R.; Roark, Ryan S.; Schmidt, Stephen D.; Sutton, Matthew S.; Louder, Mark K.; Chuang, Gwo-Yu.; Bailer, Robert T.; Cortez, Valerie.; Kong, Rui.; McKee, Krisha.; O'Dell, Sijy.; Wang, Felicia.; Abdool Karim, Salim Safurdeen.; Binley, James M.; Connors, Mark.; Haynes, Barton F.; Martin, Malcolm A.; Montefiori, David Charles.; Morris, Lynn.; Overbaugh, Julie.; Kwong, Peter D.; Mascola, John R.; Georgiev, Ivelin S.
Abstract available in pdf.
Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.
(American Association for the Advancement of Science., 2017) Alam, Shabnam Munir.; Aussedat, Baptiste.; Vohra, Yusuf.; Meyerhoff, Robert Ryan.; Cale, Evan M.; Walkowicz, William E.; Radakovich, Nathan A.; Anasti, Kara.; Armand, Lawrence.; Parks, Robert.; Sutherland, Laura L.; Scearce, Richard M.; Joyce, M. Gordon.; Pancera, Marie.; Druz, Aliaksandr.; Georgiev, Ivelin S.; Von Holle, Tarra.; Eaton, Amanda.; Fox, Christopher.; Reed, Steven G.; Louder, Mark K.; Bailer, Robert T.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Cohen, Myron S.; Liao, Hua-Xin.; Montefiori, David Charles.; Park, Peter K.; Fernández-Tejada, Alberto.; Wiehe, Kevin.; Santra, Sampa.; Kepler, Thomas B.; Saunders, Kevin O.; Sodroski, Joseph.; Kwong, Peter D.; Mascola, John R.; Bonsignori, Mattia.; Moody, Michael Anthony.; Danishefsky, Samuel.; Haynes, Barton F.
Abstract available in pdf.
New member of the V1V2-directed CAP256-VRC26 lineage that shows increased breadth and exceptional potency.
(American Society for Microbiology., 2016) Doria-Rose, Nicole A.; Bhiman, Jinal N.; Roark, Ryan S.; Schramm, Chaim A.; Gorman, Jason.; Chuang, Gwo-Yu.; Pancera, Marie.; Cale, Evan M.; Ernandes, Michael J.; Louder, Mark K.; Asokan, Mangaiarkarasi.; Bailer, Robert T.; Druz, Aliaksandr.; Fraschilla, Isabella R.; Garrett, Nigel Joel.; Jarosinski, Marissa.; Lynch, Rebecca M.; McKee, Krisha.; O’Dell, Sijy.; Pegu, Amarendra.; Schmidt, Stephen D.; Staupe, Ryan P.; Sutton, Matthew S.; Wang, Keyun.; Wibmer, Constantinos Kurt.; Haynes, Barton F.; Abdool Karim, Salim Safurdeen.; Shapiro, Lawrence.; Kwong, Peter D.; Moore, Penelope L.; Morris, Lynn.; Mascola, John R.
Abstract available in pdf.
Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.
(American Association for the Advancement of Science., 2017) Williams, LaTonya D.; Ofek, Gilad.; Schätzle, Sebastian.; McDaniel, Jonathan R.; Lu, Xiaozhi.; Nicely, Nathan I.; Wu, Liming; Lougheed, Caleb S.; Bradley, Todd.; Louder, Mark K.; McKee, Krisha.; Bailer, Robert T.; O’Dell, Sijy.; Georgiev, Ivelin S.; Seaman, Michael S.; Parks, Robert J.; Marshall, Dawn J.; Anasti, Kara.; Yang, Guang.; Nie, Xiaoyan.; Tumba, Nancy Lola.; Wiehe, Kevin.; Wagh, Kshitij.; Korber, Bette T. M.; Kepler, Thomas B.; Alam, Shabnam Munir.; Morris, Lynn.; Kamanga, Gift.; Cohen, Myron S.; Bonsignori, Mattia.; Xia, Shi-Mao.; Montefiori, David Charles.; Kelsoe, Garnett.; Gao, Feng.; Mascola, John R.; Moody, Michael Anthony.; Saunders, Kevin O.; Liao, Hua-Xin.; Tomaras, Georgia D.; Georgiou, George.; Haynes, Barton F.
Abstract available in pdf.
Structure and immune recognition of trimeric pre-fusion HIV-1 Env.
(Macmillan Publishers Limited., 2014) Pancera, Marie.; Zhou, Tongqing.; Druz, Aliaksandr.; Georgiev, Ivelin S.; Soto, Cinque.; Gorman, Jason.; Huang, Jinghe.; Acharya, Priyamvada.; Chuang, Gwo-Yu.; Ofek, Gilad.; Stewart-Jones, Guillaume B. E.; Stuckey, Jonathan.; Bailer, Robert T.; Joyce, M. Gordon.; Louder, Mark K.; Tumba, Nancy Lola.; Yang, Yongping.; Zhang, Baoshan.; Cohen, Myron S.; Haynes, Barton F.; Mascola, John R.; Morris, Lynn.; Munro, James B.; Blanchard, Scott C.; Mothes, Walther.; Connors, Mark.; Kwong, Peter D.
The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.
Structure of an N276-dependent HIV-1 neutralizing antibody targeting a rare V5 glycan hole adjacent to the CD4 binding site.
(American Society for Microbiology., 2016) Wibmer, Constantinos Kurt.; Gorman, Jason.; Anthony, Colin S.; Mkhize, Nonhlanhla N.; Druz, Aliaksandr.; York, Talita.; Schmidt, Stephen D.; Labuschagne, Phillip.; Louder, Mark K.; Bailer, Robert T.; Abdool Karim, Salim Safurdeen.; Mascola, John R.; Williamson, Carolyn.; Moore, Penelope L.; Kwong, Peter D.; Morris, Lynn.
Abstract available in pdf.