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Journal of Virology, June 2004, p. 5651-5657, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5651-5657.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Increased Sensitivity to CD4 Binding Site-Directed Neutralization following In Vitro Propagation on Primary Lymphocytes of a Neutralization-Resistant Human Immunodeficiency Virus IIIB Strain Isolated from an Accidentally Infected Laboratory Worker

Tim Beaumont,1,{dagger} Esther Quakkelaar,1 Ad van Nuenen,1 Ralph Pantophlet,2 and Hanneke Schuitemaker1*

Department of Clinical Viro-Immunology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, The Netherlands,1 Department of Immunology, Scripps Research Institute, La Jolla, California 920372

Received 16 December 2003/ Accepted 30 January 2004

We previously described the adaptation of the neutralization-sensitive human immunodeficiency virus type 1 (HIV-1) strain IIIB to a neutralization-resistant phenotype in an accidentally infected laboratory worker. During long-term propagation of this resistant isolate, designated FF3346, on primary peripheral blood leukocytes in vitro, an HIV-1 variant appeared that had regained sensitivity to neutralization by soluble CD4 (sCD4) and the broadly neutralizing monoclonal antibody b12. When an early passage of FF3346 was subjected to limiting-dilution culture in peripheral blood mononuclear cells, eight virus variants with various degrees of neutralization resistance were isolated. Two of them, the sCD4 neutralization-resistant variant LW_H8res and the sCD4 neutralization-sensitive variant LW_G9sens, were selected for further study. Interestingly, these two viruses were equally resistant to neutralization by agents that recognize domains other than the CD4 binding site. Site-directed mutagenesis revealed that the increased neutralization sensitivity of variant LW_G9sens resulted from only two changes, an Asn-to-Ser substitution at position 164 in the V2 loop and an Ala-to-Glu substitution at position 370 in the C3 domain of gp120. In agreement with this notion, the affinity of b12 for monomeric gp120 containing the N164S and A370E substitutions in the background of the molecular clone LW_H8res was higher than its affinity for the parental gp120. Surprisingly, no correlation was observed between CD4 binding affinity for monomeric gp120 and the level of neutralization resistance, suggesting that differences in sCD4 neutralization sensitivity between these viruses are only manifested in the context of the tertiary or quaternary structure of gp120 on the viral surface. The results obtained here indicate that the neutralization-sensitive strain IIIB can become neutralization resistant in vivo under selective pressure by neutralizing antibodies but that this resistance may be easily reversed in the absence of immunological pressure.

* Corresponding author. Mailing address: Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. Phone: 31 20 5123317. Fax: 31 20 5123310. E-mail: h.schuitemaker{at}sanquin.nl.

{dagger} Present address: Gladstone Institute of Virology and Immunology, University of California, San Francisco.

Journal of Virology, June 2004, p. 5651-5657, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5651-5657.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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