Browsing by Author "Mascola, John R."

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Broad neutralization of human immunodeficiency virus type 1 mediated by plasma antibodies against the gp41 membrane proximal external region.
(American Society for Microbiology., 2009) Gray, Elin Solomonovna.; Madiga, Maphuti C.; Moore, Penelope L.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Binley, James M.; Shaw, George M.; Mascola, John R.; Morris, Lynn.
We identified three cross-neutralizing plasma samples with high-titer anti-membrane proximal external region (MPER) peptide binding antibodies from among 156 chronically human immunodeficiency virus type 1-infected individuals. In order to establish if these antibodies were directly responsible for the observed neutralization breadth, we used MPER-coated magnetic beads to deplete plasmas of these specific antibodies. Depletion of anti-MPER antibodies from BB34, CAP206, and SAC21 resulted in 77%, 68%, and 46% decreases, respectively, in the number of viruses neutralized. Antibodies eluted from the beads showed neutralization profiles similar to those of the original plasmas, with potencies comparable to those of the known anti-MPER monoclonal antibodies (MAbs), 4E10, 2F5, and Z13e1. The anti-MPER neutralizing antibodies in BB34 were present in the immunoglobulin G3 subclass-enriched fraction. Alanine scanning of the MPER showed that the antibodies from these three plasmas had specificities distinct from those of the known MAbs, requiring one to three crucial residues at positions 670, 673, and 674. These data demonstrate the existence of MPER-specific cross-neutralizing antibodies in plasma, although the ability to elicit such potent antiviral antibodies during natural infection appears to be rare. Nevertheless, the identification of three novel antibody specificities within the MPER supports its further study as a promising target for vaccine design.
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.
The development of CD4 binding site antibodies during HIV-1 infection.
(American Society for Microbiology., 2012) Lynch, Rebecca M.; Tran, Lillian.; Louder, Mark K.; Schmidt, Stephen D.; Cohen, Myron S.; DerSimonian, Rebecca.; Euler, Zelda.; Gray, Elin Solomonovna.; Abdool Karim, Salim Safurdeen.; Kirchherr, Jennifer.; Montefiori, David Charles.; Sibeko, Sengeziwe.; Soderberg, Kelly.; Tomaras, Georgia D.; Yang, Zhi-Yong.; Nabel, Gary J.; Schuitemaker, Hanneke.; Morris, Lynn.; Haynes, Barton F.; Mascola, John R.
Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.
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.
Immunoglobulin gene insertions and deletions in the affinity maturation of HIV-1 broadly reactive neutralizing antibodies.
(Cell Press., 2014) Kepler, Thomas B.; Liao, Hua-Xin.; Alam, Shabnam Munir.; Bhaskarabhatla, Rekha.; Zhang, Ruijun.; Yandava, Chandri.; Stewart, Shelley.; Anasti, Kara.; Kelsoe, Garnett.; Parks, Robert.; Lloyd, Krissey E.; Stolarchuk, Christina.; Pritchett, Jamie.; Solomon, Erika.; Friberg, Emma.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Cohen, Myron S.; Walter, Emmanuel.; Moody, Michael Anthony.; Wu, Xueling.; Altae-Tran, Han R.; Georgiev, Ivelin S.; Kwong, Peter D.; Boyd, Scott D.; Fire, Andrew Z.; Mascola, John R.; Haynes, Barton F.
Abstract available in pdf.
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.
Optimal combinations of broadly neutralizing antibodies for prevention and treatment of HIV-1 clade C infection.
(Public Library of Science., 2016) Wagh, Kshitij.; Bhattacharya, Tanmoy.; Williamson, Carolyn.; Robles, Alexander.; Bayne, Madeleine.; Garrity, Jetta.; Rist, Michael.; Rademeyer, Cecilia.; Yoon, Hyejin.; Lapedes, Alan.; Gao, Hongmei.; Greene, Kelli M.; Louder, Mark K.; Kong, Rui.; Abdool Karim, Salim Safurdeen.; Burton, Dennis R.; Barouch, Dan H.; Nussenzweig, Michel C.; Mascola, John R.; Morris, Lynn.; Montefiori, David Charles.; Korber, Bette T. M.; Seaman, Michael S.
Abstract available in PDF file.
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.
Recommendations for the design and use of standard virus panels to assess neutralizing antibody responses elicited by candidate Human Immunodeficiency Virus Type 1 vaccines.
(American Society for Microbiology., 2005) Mascola, John R.; D'Souza, Patricia.; Gilbert, Peter B.; Hahn, Beatrice H.; Haigwood, Nancy L.; Morris, Lynn.; Petropoulos, Christos J.; Polonis, Victoria R.; Sarzotti, Marcella.; Montefiori, David Charles.
No abstract available.
Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation.
(Nature Publishing Group., 2018) Johnson, Erik L.; Doria-Rose, Nicole A.; Gorman, Jason.; Bhiman, Jinal N.; Schramm, Chaim A.; Vu, Ashley Q.; Law, William H.; Zhang, Baoshan.; Bekker, Valerie.; Abdool Karim, Salim Safurdeen.; Ippolito, Gregory C.; Morris, Lynn.; Moore, Penelope L.; Kwong, Peter D.; Mascola, John R.; Georgiou, George.
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 and recognition of a novel HIV-1 gp120-gp41 interface antibody that caused MPER exposure through viral escape.
(Public Library of Science., 2017) Wibmer, Constantinos Kurt.; Gorman, Jason.; Ozorowski, Gabriel.; Bhiman, Jinal N.; Sheward, Daniel J.; Elliott, Debra H.; Rouelle, Julie.; Smira, Ashley.; Joyce, M. Gordon.; Ndabambi, Nonkululeko.; Druz, Aliaksandr.; Asokan, Mangaiarkarasi.; Burton, Dennis R.; Connors, Mark.; Abdool Karim, Salim Safurdeen.; Mascola, John R.; Robinson, James E.; Ward, Andrew B.; Williamson, Carolyn.; Kwong, Peter D.; Morris, Lynn.; Moore, Penelope L.
Abstract available in pdf.
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.
Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies.
(Nature Publishing Group., 2015) Bhiman, Jinal N.; Anthony, Colin S.; Doria-Rose, Nicole A.; Karimanzira, Owen.; Schramm, Chaim A.; Khoza, Thandeka.; Kitchin, Dale.; Botha, Gordon.; Gorman, Jason.; Garrett, Nigel Joel.; Abdool Karim, Salim Safurdeen.; Shapiro, Lawrence.; Williamson, Carolyn.; Kwong, Peter D.; Mascola, John R.; Morris, Lynn.; Moore, Penelope L.
Abstract available in pdf.
Which new health technologies do we need to achieve an end to HIV/AIDS?
(Public Library of Science., 2016) Gray, Glenda Elizabeth.; Laher, Faatima.; Doherty, Tanya.; Abdool Karim, Salim Safurdeen.; Hammer, Scott.; Mascola, John R.; Beyrer, Chris.; Corey, Larry.
Abstract available in PDF file.