Browsing by Author "Montefiori, David Charles."

Now showing 1 - 15 of 15

Amino acid changes in the HIV-1 gp41 membrane proximal region control virus neutralization sensitivity.
(Elsevier., 2016) Bradley, Todd.; Trama, Ashley.; Tumba, Nancy Lola.; Gray, Elin Solomonovna.; Lu, Xiaozhi.; Madani, Navid.; Jahanbakhsh, Fatemeh.; Eaton, Amanda.; Xia, Shi-Mao.; Parks, Robert.; Lloyd, Krissey E.; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy M.; Barnett, Susan.; Abdool Karim, Salim Safurdeen.; Boyd, Scott D.; Melillo, Bruno.; Smith, Amos B.; Sodroski, Joseph.; Kepler, Thomas B.; Alam, Shabnam Munir.; Gao, Feng.; Bonsignori, Mattia.; Liao, Hua-Xin.; Moody, Michael Anthony.; Montefiori, David Charles.; Santra, Sampa.; Morris, Lynn.; Haynes, Barton F.
Abstract available in pdf.
Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved.
(Cell Press., 2014) Wiehe, Kevin.; Easterhoff, David.; Luo, Kan.; Nicely, Nathan I.; Bradley, Todd.; Jaeger, Frederick H.; Dennison, Sally Moses.; Zhang, Ruijun.; Lloyd, Krissey E.; Stolarchuk, Christina.; Parks, Robert.; Sutherland, Laura L.; Scearce, Richard M.; Morris, Lynn.; Kaewkungwal, Jaranit.; Nitayaphan, Sorachai.; Pitisuttithum, Punnee.; Rerks-Ngarm, Supachai.; Sinangil, Faruk.; Phogat, Sanjay.; Michael, Nelson L.; Kim, Jerome H.; Kelsoe, Garnett.; Montefiori, David Charles.; Tomaras, Georgia D.; Bonsignori, Mattia.; Santra, Sampa.; Kepler, Thomas B.; Alam, Shabnam Munir.; Moody, Michael Anthony.; Liao, Hua-Xin.; Haynes, Barton F.
Abstract available in pdf.
Comparison of viral env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design.
(American Society for Microbiology., 2013) Ping, Li-Hua.; Joseph, Sarah B.; Anderson, Jeffrey A.; Abrahams, Melissa-Rose.; Salazar-Gonzalez, Jesus F.; Kincer, Laura P.; Treurnicht, Florette K.; Arney, Leslie.; Ojeda, Suany.; Zhang, Ming.; Keys, Jessica.; Potter, E. Lake.; Chu, Haitao.; Moore, Penelope L.; Salazar-Gonzalez, Maria.; Iyer, Shilpa.; Jabara, Cassandra.; Kirchherr, Jennifer.; Mapanje, Clement.; Ngandu, Nobubelo K.; Seoighe, Cathal.; Hoffman, Irving F.; Gao, Feng.; Tang, Yuyang.; Labranche, Celia.; Lee, Benhur.; Saville, Andrew.; Vermeulen, Marion.; Fiscus, Susan A.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Shaw, George M.; Korber, Bette T. M.; Hahn, Beatrice H.; Cohen, Myron S.; Montefiori, David Charles.; Williamson, Carolyn.; Swanstrom, Ronald.
Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine.We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission.We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell.We confirmed an earlier observation that the transmitted viruses were, on average, modestly under-glycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event.We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies.We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.
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.
Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition : implications for active and passive immunization.
(Public Library of Science., 2016) Rademeyer, Cecilia.; Korber, Bette T. M.; Seaman, Michael S.; Giorgi, Elena E.; Thebus, Ruwayhida.; Robles, Alexander.; Sheward, Daniel J.; Wagh, Kshitij.; Garrity, Jetta.; Carey, Brittany R.; Gao, Hongmei.; Greene, Kelli M.; Tang, Haili.; Bandawe, Gama P.; Marais, Jinny C.; Diphoko, Thabo E.; Hraber, Peter.; Tumba, Nancy Lola.; Moore, Penelope L.; Gray, Glenda Elizabeth.; Kublin, James.; McElrath, Margaret Juliana.; Vermeulen, Marion.; Middelkoop, Keren.; Bekker, Linda-Gail.; Hoelscher, Michael.; Maboko, Leonard.; Makhema, Joseph.; Robb, Merlin L.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Kim, Jerome H.; Hahn, Beatrice H.; Gao, Feng.; Swanstrom, Ronald.; Morris, Lynn.; Montefiori, David Charles.; Williamson, Carolyn.
Abstract available in PDF file.
High titer HIV-1 V3-specific antibodies with broad reactivity but low neutralizing potency in acute infection and following vaccination.
(Elsevier, 2008) Davis, Katie L.; Gray, Elin Solomonovna.; Moore, Penelope L.; Decker, Julie M.; Salomon, Aidy.; Montefiori, David Charles.; Graham, Barney S.; Keefer, Michael C.; Pinter, Abraham.; Morris, Lynn.; Hahn, Beatrice H.; Shaw, George M.
Identifying the earliest neutralizing antibody specificities that are elicited following infection or vaccination by HIV-1 is an important objective of current HIV/AIDS vaccine research. We have shown previously that transplantation of HIV-1 V3 epitopes into an HIV-2 envelope (Env) scaffold provides a sensitive and specific means to detect and quantify HIV-1 V3 epitope specific neutralizing antibodies (Nabs) in human sera. Here, we employ this HIV-2/HIV-1 V3 scaffolding strategy to study the kinetics of development and breadth of V3- specific Nabs in longitudinal sera from individuals acutely infected with clade C or clade B HIV-1 and in human subjects immunized with clade B HIV-1 immunogens. HIV-2/HIV-1 chimeras containing V3 sequences matched to virus type (HIV-2 or HIV-1), subtype (clade B or C), or strain (autologous or heterologous) were used as test reagents. We found that by 3–8 weeks post infection, 12 of 14 clade C subjects had a median IC50 V3-specific Nab titer of 1:700 against chimeric viruses containing a heterologous clade C V3. By 5 months post-infection, all 14 subjects were positive for V3-specific Nabs with median titers of 1:8000 against heterologous clade C V3 and 1:1300 against clade B V3. Two acutely infected clade B patients developed heterologous clade B V3-specific Nabs at titers of 1:300 and 1:1800 by 13 weeks of infection and 1:5000 and 1:11000 by 7 months of infection. Titers were not different against chimeras containing autologous clade B V3 sequences. Each of 10 uninfected normal human volunteers who were immunized with clade B HIV-1 Env immunogens, but none of five sham immunized control subjects, developed V3-specific Nabs titers as high as 1:3000 (median 1:1300; range 1:700–1:3000). None of the HIV- 1 infected or vaccinated subjects had antibodies that neutralized primary HIV-1 virus strains. These results indicate that high-titer, broadly reactive V3-specific antibodies are among the first to be elicited during acute and early HIV-1 infection and following vaccination but these antibodies lack neutralizing potency against primary HIV-1 viruses, which effectively shield V3 from antibody binding to the functional Env trimer.
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.
Initial B-Cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia.
(American Society for Microbiology., 2008) Tomaras, Georgia D.; Yates, Nicole L.; Liu, Pinghuang.; Qin, Li.; Fouda, Genevieve Giny.; Chavez, Leslie L.; Decamp, Allan C.; Parks, Robert J.; Ashley, Vicki C.; Lucas, Judith T.; Cohen, Myron S.; Eron, Joseph J.; Hick, Charles B.; Liao, Hua-Xin.; Self, Steven G.; Landucci, Gary.; Forthal, Donald N.; Weinhold, Kent J.; Keele, Brandon F.; Hahn, Beatrice H.; Greenberg, Michael L.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Blattner, William A.; Montefiori, David Charles.; Shaw, George M.; Perelson, Alan S.; Haynes, Barton F.
A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.
Isolation of a human anti-HIV gp41 membrane proximal region neutralizing antibody by antigen-specific single B cell sorting.
(Plos., 2011) Morris, Lynn.; Chen, Xi.; Alam, Shabnam Munir.; Tomaras, Georgia D.; Zhang, Ruijun.; Marshall, Dawn J.; Chen, Bing.; Parks, Robert J.; Foulger, Andrew.; Jaeger, Frederick H.; Donathan, Michele.; Bilska, Mira.; Gray, Elin Solomonovna.; Abdool Karim, Salim Safurdeen.; Kepler, Thomas B.; Whitesides, John.; Montefiori, David Charles.; Moody, Michael Anthony.; Liao, Hua-Xin.; Haynes, Barton F.
Broadly neutralizing antibodies are not commonly produced in HIV-1 infected individuals nor by experimental HIV-1 vaccines. When these antibodies do occur, it is important to be able to isolate and characterize them to provide clues for vaccine design. CAP206 is a South African subtype C HIV-1-infected individual previously shown to have broadly neutralizing plasma antibodies targeting the envelope gp41 distal membrane proximal external region (MPER). We have now used a fluoresceinated peptide tetramer antigen with specific cell sorting to isolate a human neutralizing monoclonal antibody (mAb) against the HIV-1 envelope gp41 MPER. The isolated recombinant mAb, CAP206-CH12, utilized a portion of the distal MPER (HXB2 amino acid residues, 673–680) and neutralized a subset of HIV-1 pseudoviruses sensitive to CAP206 plasma antibodies. Interestingly, this mAb was polyreactive and used the same germ-line variable heavy (VH1-69) and variable kappa light chain (VK3-20) gene families as the prototype broadly neutralizing anti-MPER mAb, 4E10 (residues 672–680). These data indicate that there are multiple immunogenic targets in the C-terminus of the MPER of HIV-1 gp41 envelope and suggests that gp41 neutralizing epitopes may interact with a restricted set of naive B cells during HIV-1 infection.
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.
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.
Structural constraints of vaccine-induced tier-2 autologous HIV neutralizing antibodies targeting the receptor-binding site.
(Cell Press., 2016) Bradley, Todd.; Fera, Daniela.; Bhiman, Jinal N.; Eslamizar, Leila.; Lu, Xiaozhi.; Anasti, Kara.; Zhang, Ruijun.; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy M.; Stolarchuk, Christina.; Lloyd, Krissey E.; Parks, Robert.; Eaton, Amanda.; Foulger, Andrew.; Nie, Xiaoyan.; Abdool Karim, Salim Safurdeen.; Barnett, Susan.; Kelsoe, Garnett.; Kepler, Thomas B.; Alam, Shabnam Munir.; Montefiori, David Charles.; Moody, Michael Anthony.; Liao, Hua-Xin.; Morris, Lynn.; Santra, Sampa.; Harrison, Stephen C.; Haynes, Barton F.
Abstract available in pdf.