Emergence of monoclonal antibody b12-resistant human immunodeficiency virus type 1 variants during natural infection in the absence of humoral or cellular immune pressure

Evelien M Bunnik, Marit J. Van Gils, Marilie S.D. Lobbrecht, Linaida Pisas, Nening M. Nanlohy, Debbie Van Baarle, Ad C. Van Nuenen, Ann J. Hessell, Hanneke Schuitemaker

Research output: Contribution to journalArticle

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Abstract

Human immunodeficiency virus type 1 (HIV-1) resistance to broadly neutralizing antibodies such as b12, which targets the highly conserved CD4-binding site, raises a significant hurdle for the development of a neutralizing antibody-based vaccine. Here, 15 individuals were studied of whom seven developed b12-resistant viruses late in infection. The study investigated whether immune pressure may be involved in the selection of these viruses in vivo. Although four out of seven patients showed HIV-1-specific broadly neutralizing activity in serum, none of these patients had CD4-binding site-directed antibodies, indicating that strong humoral immunity is not a prerequisite for the outgrowth of b12-resistant viruses. In virus variants from one patient, who showed extremely weak heterologous and autologous neutralizing activity in serum, mutations were identified in the envelope that coincided with changes in b12 neutralization sensitivity. Lack of cytotoxic T-cell activity against epitopes with and without these mutations excluded a role for host cellular immunity in the selection of b12-resistant mutant viruses in this patient. However, b12 resistance correlated well with increased virus replication kinetics, indicating that selection for enhanced infectivity, possibly driven by the low availability of target cells in the later stages of disease, may coincide with increased resistance to CD4-binding site-directed agents, such as b12. These results showed that b12-resistant HIV-1 variants can emerge during the course of natural infection in the absence of both humoral and cellular immune pressure, suggestive of other mechanisms playing a role in the selective outgrowth of b12-resistant viruses.

Original languageEnglish (US)
Pages (from-to)1354-1364
Number of pages11
JournalJournal of General Virology
Volume91
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

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HIV-1
Monoclonal Antibodies
Viruses
Pressure
Infection
Neutralizing Antibodies
Binding Sites
Antibody Binding Sites
Mutation
Humoral Immunity
Virus Replication
Serum
Cellular Immunity
Epitopes
Vaccines
T-Lymphocytes

ASJC Scopus subject areas

  • Virology

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Emergence of monoclonal antibody b12-resistant human immunodeficiency virus type 1 variants during natural infection in the absence of humoral or cellular immune pressure. / Bunnik, Evelien M; Van Gils, Marit J.; Lobbrecht, Marilie S.D.; Pisas, Linaida; Nanlohy, Nening M.; Van Baarle, Debbie; Van Nuenen, Ad C.; Hessell, Ann J.; Schuitemaker, Hanneke.

In: Journal of General Virology, Vol. 91, No. 5, 01.05.2010, p. 1354-1364.

Research output: Contribution to journalArticle

Bunnik, Evelien M ; Van Gils, Marit J. ; Lobbrecht, Marilie S.D. ; Pisas, Linaida ; Nanlohy, Nening M. ; Van Baarle, Debbie ; Van Nuenen, Ad C. ; Hessell, Ann J. ; Schuitemaker, Hanneke. / Emergence of monoclonal antibody b12-resistant human immunodeficiency virus type 1 variants during natural infection in the absence of humoral or cellular immune pressure. In: Journal of General Virology. 2010 ; Vol. 91, No. 5. pp. 1354-1364.
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