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Pathogenesis and Immunity

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

Elin S. Gray, Maphuti C. Madiga, Tandile Hermanus, Penny L. Moore, Constantinos Kurt Wibmer, Nancy L. Tumba, Lise Werner, Koleka Mlisana, Sengeziwe Sibeko, Carolyn Williamson, Salim S. Abdool Karim, Lynn Morris, and the CAPRISA002 Study Team
Elin S. Gray
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
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Maphuti C. Madiga
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
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Tandile Hermanus
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
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Penny L. Moore
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
2University of Witwatersrand, Johannesburg, South Africa
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Constantinos Kurt Wibmer
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
2University of Witwatersrand, Johannesburg, South Africa
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Nancy L. Tumba
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
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Lise Werner
3Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa
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Koleka Mlisana
3Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa
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Sengeziwe Sibeko
3Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa
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Carolyn Williamson
4Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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Salim S. Abdool Karim
3Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa
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Lynn Morris
1AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa
2University of Witwatersrand, Johannesburg, South Africa
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  • For correspondence: lynnm@nicd.ac.za
DOI: 10.1128/JVI.00198-11
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ABSTRACT

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.

  • Copyright © 2011, American Society for Microbiology
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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
Elin S. Gray, Maphuti C. Madiga, Tandile Hermanus, Penny L. Moore, Constantinos Kurt Wibmer, Nancy L. Tumba, Lise Werner, Koleka Mlisana, Sengeziwe Sibeko, Carolyn Williamson, Salim S. Abdool Karim, Lynn Morris, and the CAPRISA002 Study Team
Journal of Virology Apr 2011, 85 (10) 4828-4840; DOI: 10.1128/JVI.00198-11

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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
Elin S. Gray, Maphuti C. Madiga, Tandile Hermanus, Penny L. Moore, Constantinos Kurt Wibmer, Nancy L. Tumba, Lise Werner, Koleka Mlisana, Sengeziwe Sibeko, Carolyn Williamson, Salim S. Abdool Karim, Lynn Morris, and the CAPRISA002 Study Team
Journal of Virology Apr 2011, 85 (10) 4828-4840; DOI: 10.1128/JVI.00198-11
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