Browsing by Author "Hermanus, Tandile."

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Characterization of anti-HIV-1 neutralizing and binding antibodies in chronic HIV-1 subtype C infection.
(Elsevier., 2012) Archary, Derseree.; Rong, Rong.; Gordon, Michelle Lucille.; Boliar, Saikat.; Madiga, Maphuti C.; Gray, Elin Solomonovna.; Dugast, Anne-Sophie.; Hermanus, Tandile.; Goulder, Philip Jeremy Renshaw.; Coovadia, Hoosen Mahomed.; Werner, Lise.; Morris, Lynn.; Alter, Galit.; Derdeyn, Cynthia A.; Ndung'u, Peter Thumbi.
Neutralizing (nAbs) and high affinity binding antibodies may be critical for an efficacious HIV-1 vaccine. We characterized virus-specific nAbs and binding antibody responses over 21 months in eight HIV-1 subtype C chronically infected individuals with heterogeneous rates of disease progression. Autologous nAb titers of study exit plasma against study entry viruses were significantly higher than contemporaneous responses at study entry (p=0.002) and exit (p=0.01). NAb breadth and potencies against subtype C viruses were significantly higher than for subtype A (p=0.03 and p=0.01) or B viruses (p=0.03; p=0.05) respectively. Gp41-IgG binding affinity was higher than gp120-IgG (p=0.0002). IgG–FcγR1 affinity was significantly higher than FcγRIIIa (p<0.005) at study entry and FcγRIIb (p<0.05) or FcγRIIIa (p<0.005) at study exit. Evolving IgG binding suggests alteration of immune function mediated by binding antibodies. Evolution of nAbs was a potential marker of HIV-1 disease progression.
Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape.
(Nature Publishing Group., 2012) Moore, Penelope L.; Gray, Elin Solomonovna.; Wibmer, Constantinos Kurt.; Bhiman, Jinal N.; Nonyane, Molati.; Hermanus, Tandile.; Sheward, Daniel J.; Bajimaya, Shringkhala.; Abrahams, Melissa-Rose.; Tumba, Nancy Lola.; Ping, Li-Hua.; Ngandu, Nobubelo K.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Swanstrom, Ronald.; Seaman, Michael S.; Williamson, Carolyn.; Morris, Lynn.;
Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.
Multiple pathways of escape from HIV broadly cross-neutralizing V2-dependent antibodies.
(American Society for Microbiology., 2012) Moore, Penelope L.; Sheward, Daniel J.; Nonyane, Molati.; Ranchobe, Nthabeleng.; Hermanus, Tandile.; Gray, Elin Solomonovna.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Morris, Lynn.
Broadly cross-neutralizing (BCN) antibodies are likely to be critical for an effective HIV vaccine. However, the ontogeny of such antibodies and their relationship with autologous viral evolution is unclear. Here, we characterized viral evolution in CAP256, a subtype C-infected individual who developed potent BCN antibodies targeting positions R166 and K169 in the V2 region. CAP256 was superinfected at 3 months postinfection with a virus that was highly sensitive to BCN V2-dependent monoclonal antibodies. The autologous neutralizing response in CAP256 was directed at V1V2, reaching extremely high titers (>1:40,000) against the superinfecting virus at 42 weeks, just 11 weeks prior to the development of the BCN response targeting the same region. Recombination between the primary and superinfecting viruses, especially in V2 and gp41, resulted in two distinct lineages by 4 years postinfection. Although neutralization of some CAP256 clones by plasma from as much as 2 years earlier suggested incomplete viral escape, nonetheless titers against later clones were reduced at least 40-fold to less than 1:1,000. Escape mutations were identified in each lineage, either at R166 or at K169, suggesting that strain-specific and BCN antibodies targeted overlapping epitopes. Furthermore, the early dependence of CAP256 neutralizing antibodies on the N160 glycan decreased with the onset of neutralization breadth, indicating a change in specificity. These data suggest rapid maturation, within 11 weeks, of CAP256 strain-specific antibodies to acquire breadth, with implications for the vaccine elicitation of BCN V2-dependent antibodies. Overall these studies demonstrate that ongoing viral escape is possible, even from BCN antibodies.
The Neutralization Breadth of HIV-1 Develops Incrementally over Four Years and Is Associated with CD4+ T Cell Decline and High Viral Load during Acute Infection.
(American Society for Microbiology., 2011) Gray, Elin Solomonovna.; Madiga, Maphuti C.; Hermanus, Tandile.; Moore, Penelope L.; Wibmer, Constantinos Kurt.; Tumba, Nancy Lola.; Werner, Lise.; Mlisana, Koleka Patience.; Sibeko, Sengeziwe.; Williamson, Carolyn.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.
An understanding of how broadly neutralizing activity develops in HIV-1-infected individuals is needed to guide vaccine design and immunization strategies. Here we used a large panel of 44 HIV-1 envelope variants (subtypes A, B, and C) to evaluate the presence of broadly neutralizing antibodies in serum samples obtained 3 years after seroconversion from 40 women enrolled in the CAPRISA 002 acute infection cohort. Seven of 40 participants had serum antibodies that neutralized more than 40% of viruses tested and were considered to have neutralization breadth. Among the samples with breadth, CAP257 serum neutralized 82% (36/44 variants) of the panel, while CAP256 serum neutralized 77% (33/43 variants) of the panel. Analysis of longitudinal samples showed that breadth developed gradually starting from year 2, with the number of viruses neutralized as well as the antibody titer increasing over time. Interestingly, neutralization breadth peaked at 4 years postinfection, with no increase thereafter. The extent of cross-neutralizing activity correlated with CD4+T cell decline, viral load, and CD4+T cell count at 6 months postinfection but not at later time points, suggesting that early events set the stage for the development of breadth. However, in a multivariate analysis, CD4 decline was the major driver of this association, as viral load was not an independent predictor of breadth. Mapping of the epitopes targeted by cross-neutralizing antibodies revealed that in one individual these antibodies recognized the membrane-proximal external region (MPER), while in two other individuals, cross-neutralizing activity was adsorbed by monomeric gp120 and targeted epitopes that involved the N-linked glycan at position 332 in the C3 region. Serum antibodies from the other four participants targeted quaternary epitopes, at least 2 of which were PG9/16-like and depended on the N160 and/or L165 residue in the V2 region. These data indicate that fewer than 20% of HIV-1 subtype C-infected individuals develop antibodies with cross-neutralizing activity after 3 years of infection and that these antibodies target different regions of the HIV-1 envelope, including as yet uncharacterized epitopes.
Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop.
(American Society for Microbiology., 2010) Moore, Penelope L.; Gray, Elin Solomonovna.; Sheward, Daniel J.; Madiga, Maphuti C.; Ranchobe, Nthabeleng.; Honnen, William J.; Nonyane, Molati.; Tumba, Nancy Lola.; Hermanus, Tandile.; Sibeko, Sengeziwe.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Pinter, Abraham.; Morris, Lynn.; Lai, Zhong.
The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers. Repair of the FN/LRD-K-K motif in resistant heterologous viruses conferred sensitivity, with titers sometimes exceeding 1:10,000. Comparison of the CAP256 epitope with that of the PG9/PG16 monoclonal antibodies suggested that these epitopes overlapped, adding to the mounting evidence that this may represent a common neutralization target that should be further investigated as a potential vaccine candidate.
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.