Browsing by Author "Haynes, Barton F."

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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.
Computational analysis of antibody dynamics identifies recent HIV-1 infection.
(American Society for Clinical Investigation., 2017) Seaton, Kelly E.; Vandergrift, Nathan A.; Deal, Aaron W.; Rountree, Wes.; Bainbridge, John.; Grebe, Eduard.; Anderson, David A.; Sawant, Sheetal.; Shen, Xiaoying.; Yates, Nicole L.; Denny, Thomas N.; Liao, Hua-Xin.; Haynes, Barton F.; Robb, Merlin L.; Parkin, Neil.; Santos, Breno R.; Garrett, Nigel Joel.; Price, Matthew A.; Naniche, Denise.; Duerr, Ann C.; Keating, Sheila.; Hampton, Dylan.; Facente, Shelley.; Marson, Kara.; Welte, Alex.; Pilcher, Christopher D.; Cohen, Myron S.; Tomaras, Georgia D.
Abstract available in pdf.
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.
HIV-1 specific IgA detected in vaginal secretions of HIV uninfected women participating in a microbicide trial in Southern Africa are primarily directed toward gp120 and gp140 specificities.
(Public Library of Science., 2014) Seaton, Kelly E.; Ballweber, Lamar.; Lan, Audrey.; Donathan, Michele.; Hughes, Sean.; Vojtech, Lucia.; Moody, Michael Anthony.; Liao, Hua-Xin.; Haynes, Barton F.; Galloway, Christine G.; Richardson, Barbra Ann.; Abdool Karim, Salim Safurdeen.; Dezzutti, Charlene S.; McElrath, Margaret Juliana.; Tomaras, Georgia D.; Hladik, Florian.
Abstract available in pdf.
HIV-Selectest enzyme immunoassay and rapid test: ability to detect seroconversion following HIV-1 infection.
(American Society for Microbiology., 2009) Khurana, Surender.; Norris, Philip J.; Busch, Michael P.; Haynes, Barton F.; Park, Susan.; Sasono, Pretty.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Hecht, Frederick M.; Mulenga, Joseph.; Chomba, Elwyn.; Hunter, Eric.; Allen, Susan.; Nemo, George.; Rodriguez-Chavez, Isaac R.; Women’s Interagency HIV Study Collaborative Study Group.; Margolick, Joseph B.; Golding, Hana.
HIV-Selectest is a serodiagnostic enzyme immunoassay (EIA), containing p6 and gp41 peptides, designed to differentiate between vaccine-induced antibodies and true infections. A rapid test version of the HIV-Selectest was developed. Both assays detected HIV antibodies in men and women within 2 to 4 weeks of infection, with sensitivity similar to third-generation EIAs.
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.
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.
Isolation of a Monoclonal Antibody That Targets the Alpha-2 Helix of gp120 and Represents the Initial Autologous Neutralizing-Antibody Response in an HIV-1 Subtype C-Infected Individual.
(American Society for Microbiology., 2011) Gray, Elin Solomonovna.; Moody, Michael Anthony.; Wibmer, Constantinos Kurt.; Chen, Xi.; Marshall, Dawn J.; Amos, Joshua.; Moore, Penelope L.; Foulger, Andrew.; Yu, Jae-Sung.; Lambson, Bronwen Elizabeth.; Abdool Karim, Salim Safurdeen.; Whitesides, John.; Tomaras, Georgia D.; Haynes, Barton F.; Morris, Lynn.; Liao, Hua-Xin.
The C3-V4 region is a major target of autologous neutralizing antibodies in HIV-1 subtype C infection. We previously identified a Center for AIDS Program of Research in South Africa (CAPRISA) participant, CAP88, who developed a potent neutralizing-antibody response within 3 months of infection that targeted an epitope in the C3 region of the HIV-1 envelope (P. L. Moore et al., PLoS Pathog. 5:e1000598, 2009). Here we showed that these type-specific antibodies could be adsorbed using recombinant gp120 from the transmitted/founder virus from CAP88 but not by gp120 made from other isolates. Furthermore, this activity could be depleted using a chimeric gp120 protein that contained only the C3 region from the CAP88 viral envelope engrafted onto the unrelated CAP63 viral envelope (called 63-88C3). On the basis of this, a differential sorting of memory B cells was performed using gp120s made from 63-88C3 and CAP63 labeled with different fluorochromes as positive and negative probes, respectively. This strategy resulted in the isolation of a highly specific monoclonal antibody (MAb), called CAP88-CH06, that neutralized the CAP88 transmitted/founder virus and viruses from acute infection but was unable to neutralize CAP88 viruses isolated at 6 and 12 months postinfection. The latter viruses contained 2 amino acid changes in the alpha-2 helix of C3 that mediated escape from this MAb. One of these changes involved the introduction of an N-linked glycan at position 339 that occluded the epitope, while the other mutation (either E343K or E350K) was a charge change. Our data validate the use of differential sorting to isolate a MAb targeting a specific epitope in the envelope glycoprotein and provided insights into the mechanisms of autologous neutralization escape.
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.
Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants.
(American Society for Microbiology., 2008) Abrahams, Melissa-Rose.; Anderson, Jeffrey A.; Giorgi, Elena E.; Seoighe, Cathal.; Mlisana, Koleka Patience.; Liu, Pinghuang.; Athreya, G. S.; Treurnicht, Florette K.; Keele, Brandon F.; Wood, N.; Salazar-Gonzalez, Jesus F.; Bhattacharya, Tanmoy.; Chu, Haitao.; Hoffman, Irving F.; Galvin, S.; Mapanje, Clement.; Kazembe, P.; Thebus, Ruwayhida.; Fiscus, Susan A.; Hide, Winston.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Shaw, George M.; Hahn, Beatrice H.; Korber, Bette T. M.; Swanstrom, Ronald.; Williamson, Carolyn.
Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.
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.
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.
V2-directed vaccine-like antibodies from HIV-1 infection identify an additional K169-binding light chain motif with broad ADCC activity.
(Cell Press., 2018) van Eeden, Charmaine.; Wibmer, Constantinos Kurt.; Scheepers, Cathrine.; Richardson, Simone I.; Nonyane, Molati.; Lambson, Bronwen Elizabeth.; Mkhize, Nonhlanhla N.; Vijayakumar, Balakrishnan.; Sheng, Zizhang.; Stanfield-Oakley, Sherry.; Bhiman, Jinal N.; Bekker, Valerie.; Hermanus, Tandile.; Mabvakure, Batsirai.; Ismail, Arshad.; Moody, Michael Anthony.; Wiehe, Kevin.; Garrett, Nigel Joel.; Abdool Karim, Salim Safurdeen.; Dirr, Heini.; Fernandes, Manuel A.; Sayed, Yasien.; Shapiro, Lawrence.; Ferrari, Guido.; Haynes, Barton F.; Moore, Penelope L.; Morris, Lynn.
Abstract available in pdf.
Vertical T cell immunodominance and epitope entropy determine HIV-1 escape.
(American Society for Clinical Investigation., 2012) Liu, Michael K. P.; Hawkins, Natalie.; Ritchie, Adam J.; Ganusov, Vitaly.; Whale, Victoria.; Brackenridge, Simon.; Li, Hui.; Pavlicek, Jeffrey W.; Cai, Fangping.; Abrahams, Melissa-Rose.; Treurnicht, Florette K.; Hraber, Peter.; Riou, Catherine.; Gray, Clive M.; Ferrari, Guido.; Tanner, Rachel.; Ping, Li-Hua.; Anderson, Jeffrey A.; Swanstrom, Ronald.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Borrow, Persephone.; Perelson, Alan S.; Shaw, George M.; Hahn, Beatrice H.; Williamson, Carolyn.; Korber, Bette T. M.; Gao, Feng.; Self, Steven G.; McMichael, Andrew.; Goonetilleke, Nilu.
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.