Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits

Delphine Malherbe, Franco Pissani, D. Noah Sather, Biwei Guo, Shilpi Pandey, William F. Sutton, Andrew B. Stuart, Harlan Robins, Byung Park, Shelly J. Krebs, Jason T. Schuman, Spyros Kalams, Ann Hessell, Nancy Haigwood

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Identifying characteristics of the human immunodeficiency virus type 1 (HIV-1) envelope that are effective in generating broad, protective antibodies remains a hurdle to HIV vaccine design. Emerging evidence of the development of broad and potent neutralizing antibodies in HIV-infected subjects suggests that founder and subsequent progeny viruses may express unique antigenic motifs that contribute to this developmental pathway. We hypothesize that over the course of natural infection, B cells are programmed to develop broad antibodies by exposure to select populations of emerging envelope quasispecies variants. To test this hypothesis, we identified two unrelated subjects whose antibodies demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in both subjects. We compared the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects. Rabbits were coimmunized four times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. The affinity of the polyclonal response increased as a function of boosting. The most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. These data have implications for vaccine development in describing a target time point to identify optimal envelope immunogens.

Original languageEnglish (US)
Pages (from-to)12949-12967
Number of pages19
JournalJournal of Virology
Volume88
Issue number22
DOIs
StatePublished - 2014

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Neutralizing Antibodies
neutralizing antibodies
neutralization
rabbits
HIV
Rabbits
Human immunodeficiency virus 1
antibodies
HIV-1
Antibodies
Infection
infection
vaccines
Viruses
env Genes
AIDS Vaccines
viruses
vaccine development
cross-sectional studies
B-lymphocytes

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. / Malherbe, Delphine; Pissani, Franco; Noah Sather, D.; Guo, Biwei; Pandey, Shilpi; Sutton, William F.; Stuart, Andrew B.; Robins, Harlan; Park, Byung; Krebs, Shelly J.; Schuman, Jason T.; Kalams, Spyros; Hessell, Ann; Haigwood, Nancy.

In: Journal of Virology, Vol. 88, No. 22, 2014, p. 12949-12967.

Research output: Contribution to journalArticle

Malherbe, D, Pissani, F, Noah Sather, D, Guo, B, Pandey, S, Sutton, WF, Stuart, AB, Robins, H, Park, B, Krebs, SJ, Schuman, JT, Kalams, S, Hessell, A & Haigwood, N 2014, 'Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits', Journal of Virology, vol. 88, no. 22, pp. 12949-12967. https://doi.org/10.1128/JVI.01812-14
Malherbe, Delphine ; Pissani, Franco ; Noah Sather, D. ; Guo, Biwei ; Pandey, Shilpi ; Sutton, William F. ; Stuart, Andrew B. ; Robins, Harlan ; Park, Byung ; Krebs, Shelly J. ; Schuman, Jason T. ; Kalams, Spyros ; Hessell, Ann ; Haigwood, Nancy. / Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. In: Journal of Virology. 2014 ; Vol. 88, No. 22. pp. 12949-12967.
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