Browsing by Author "Lambson, Bronwen Elizabeth."

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Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire.
(American Association of Immunologists., 2015) Scheepers, Cathrine.; Shrestha, Ram K.; Lambson, Bronwen Elizabeth.; Jackson, Katherine J. L.; Wright, Imogen A.; Naicker, Dshanta Dyanedi.; Goosen, Mark.; Berrie, Leigh.; Ismail, Arshad.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Moore, Penelope L.; Travers, Simon A.; Morris, Lynn.
Abstract available in pdf.
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.
Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection.
(Plos, 2009) Moore, Penelope L.; Ranchobe, Nthabeleng.; Lambson, Bronwen Elizabeth.; Gray, Elin Solomonovna.; Cave, Eleanor.; Abrahams, Melissa-Rose.; Bandawe, Gama P.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Morris, Lynn.
We previously showed that HIV-1 subtype C viruses elicit potent but highly type-specific neutralizing antibodies (nAb) within the first year of infection. In order to determine the specificity and evolution of these autologous nAbs, we examined neutralization escape in four individuals whose responses against the earliest envelope differed in magnitude and potency. Neutralization escape occurred in all participants, with later viruses showing decreased sensitivity to contemporaneous sera, although they retained sensitivity to new nAb responses. Early nAb responses were very restricted, occurring sequentially and targeting only two regions of the envelope. In V1V2, limited amino acid changes often involving indels or glycans, mediated partial or complete escape, with nAbs targeting the V1V2 region directly in 2 cases. The alpha-2 helix of C3 was also a nAb target, with neutralization escape associated with changes to positively charged residues. In one individual, relatively high titers of anti-C3 nAbs were required to drive genetic escape, taking up to 7 weeks for the resistant variant to predominate. Thereafter titers waned but were still measurable. Development of this single anti-C3 nAb specificity was associated with a 7-fold drop in HIV-1 viral load and a 4-fold rebound as the escape mutation emerged. Overall, our data suggest the development of a very limited number of neutralizing antibody specificities during the early stages of HIV-1 subtype C infection, with temporal fluctuations in specificities as escape occurs. While the mechanism of neutralization escape appears to vary between individuals, the involvement of limited regions suggests there might be common vulnerabilities in the HIV-1 subtype C transmitted envelope.
Mannose-rich glycosylation patterns on HIV-1 subtype C gp120 and sensitivity to the lectins, Griffithsin, Cyanovirin-N and Scytovirin.
(Elsevier., 2010) Alexandre, Kabamba B.; Gray, Elin Solomonovna.; Lambson, Bronwen Elizabeth.; Moore, Penelope L.; Choge, Isaac Ang'Ang'A.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; McMahon, James.; O'Keefe, Barry.; Chikwamba, Rachel.; Morris, Lynn.
Griffithsin (GRFT), Cyanovirin-N (CV-N) and Scytovirin (SVN) are lectins that inhibit HIV-1 infection by binding to multiple mannose-rich glycans on the HIV-1 envelope glycoproteins (Env). Here we show that these lectins neutralize subtype C primary virus isolates in addition to Env-pseudotyped viruses obtained from plasma and cervical vaginal lavages. Among 15 subtype C pseudoviruses, the median IC50 values were 0.4, 1.8 and 20.1 nM for GRFT, CV-N and SVN, respectively, similar to what was found for subtype B and A. Analysis of Env sequences suggested that concomitant lack of glycans at positions 234 and 295 resulted in natural resistance to these compounds, which was confirmed by site-directed mutagenesis. Furthermore, the binding sites for these lectins overlapped that of the 2G12 monoclonal antibody epitope, which is generally absent on subtype C Env. This data support further research on these lectins as potential microbicides in the context of HIV-1 subtype C infection.
South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on α4β7 for replication.
(BioMed Central., 2015) Richardson, Simone I.; Gray, Elin Solomonovna.; Mkhize, Nonhlanhla N.; Sheward, Daniel J.; Lambson, Bronwen Elizabeth.; Wibmer, Constantinos Kurt.; Masson, Lindi.; Werner, Lise.; Garrett, Nigel Joel.; Passmore, Jo-Ann Shelley.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Moore, Penelope L.; Morris, Lynn.
Abstract available in pdf.
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.