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Journal of Virology, January 2009, p. 188-199, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01583-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Frequency and Phenotype of Human Immunodeficiency Virus Envelope-Specific B Cells from Patients with Broadly Cross-Neutralizing Antibodies {triangledown}

Nicole A. Doria-Rose,1 Rachel M. Klein,1 Maura M. Manion,1 Sijy O'Dell,2 Adhuna Phogat,2 Bimal Chakrabarti,2 Claire W. Hallahan,3 Stephen A. Migueles,1 Jens Wrammert,4 Rafi Ahmed,4 Martha Nason,3 Richard T. Wyatt,2 John R. Mascola,2 and Mark Connors1*

Laboratory of Immunoregulation,1 Vaccine Research Center,2 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,3 Emory Vaccine Center, Emory University, Atlanta, Georgia 303294

Received 25 July 2008/ Accepted 8 October 2008

Induction of broadly cross-reactive neutralizing antibodies (NAb) is an important goal for a prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine. Some HIV-infected patients make a NAb response that reacts with diverse strains of HIV-1, but most candidate vaccines have induced NAb only against a subset of highly sensitive isolates. To better understand the nature of broad NAb responses that arise during natural infection, we screened patients for sera able to neutralize diverse HIV strains and explored the frequency and phenotype of their peripheral Envelope-specific B cells. We screened 113 HIV-infected patients of various clinical statuses for the prevalence of broad NAb. Sera able to neutralize at least four of five viral isolates were found in over one-third of progressors and slow progressors, but much less frequently in aviremic long-term nonprogressors. Most Env-specific antibody-secreting B cells were CD27hi CD38hi plasmablasts, and the total plasmablast frequency was higher in HIV-infected patients than in uninfected donors. We found that 0.0031% of B cells and 0.047% of plasmablasts secreted Env-specific immunoglobulin G (IgG) in an enzyme-linked immunospot (ELISPOT) assay. We developed a novel staining protocol to label HIV-specific B cells with Env gp140 protein. A total of 0.09% of B cells were found to be Env-specific by this method, a frequency far higher than that indicated by ELISPOT assay. gp140-labeled B cells were predominantly CD27+ and surface IgG+. These data describe the breadth and titer of serum NAb and the frequency and phenotype of HIV-specific B cells in a cohort of patients with broad cross-neutralizing antibody responses that are potential goals for vaccines for HIV.

* Corresponding author. Mailing address: LIR, NIAID, National Institutes of Health, Bldg. 10, Rm. 7N246, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 496-8057. Fax: (301) 480-9978. E-mail: mconnors{at}niaid.nih.gov

{triangledown} Published ahead of print on 15 October 2008.

Journal of Virology, January 2009, p. 188-199, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01583-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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