Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jul;83(14):7337-48.
doi: 10.1128/JVI.00110-09. Epub 2009 May 13.

Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm

Melissa D Simek  1 , Wasima Rida, Frances H Priddy, Pham Pung, Emily Carrow, Dagna S Laufer, Jennifer K Lehrman, Mark Boaz, Tony Tarragona-Fiol, George Miiro, Josephine Birungi, Anton Pozniak, Dale A McPhee, Olivier Manigart, Etienne Karita, André Inwoley, Walter Jaoko, Jack Dehovitz, Linda-Gail Bekker, Punnee Pitisuttithum, Robert Paris, Laura M Walker, Pascal Poignard, Terri Wrin, Patricia E Fast, Dennis R Burton, Wayne C Koff
Affiliations

Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm

Melissa D Simek et al. J Virol. 2009 Jul.

Abstract

The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC(50)) neutralization titers of >or=100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC(50) titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
Frequency of neutralization breadth, defined as an IC50 titer of ≥150 to at least one pseudovirus from four out of five clade/CRF groups, in 97 serum samples from Rwanda and Zambia.
FIG. 2.
FIG. 2.
Distribution of neutralization sensitivities of early/chronic HIV-1 Env clones on panel 2 among HIV-1-infected individuals previously identified as having broad neutralizing activity on panel 1. Each bar represents the geometric mean IC50 titer of 22 serum and plasma samples from Rwanda and Zambia. Among individuals with broad neutralizing activity, pseudovirus sensitivities varied.
FIG. 3.
FIG. 3.
Frequency of breadth, defined as an IC50 titer of ≥100 to at least four out of five clade/CRF groups, from 463 samples from Rwanda, Zambia, the United Kingdom, Australia, and Uganda.
FIG. 4.
FIG. 4.
Correlation between breadth of neutralization and number of pseudoviruses neutralized, representing the 463 samples screened on panel 3. As breadth increases, the overall probability of having a response to more than one pseudovirus both within and across clade/CRF groups also increases.
FIG. 5.
FIG. 5.
Correlation between breadth of neutralization to different clade groups representing the 463 samples screened on panel 3 and overall geometric mean IC50 neutralization titer. As breadth increases the overall probability of having a more potent response to the pseudoviruses on the screening panel also increases.
FIG. 6.
FIG. 6.
Scoring distribution of all 463 samples screened on panel 3 using scoring method 1. Each bar represents the number of samples that fell within each scoring range. A score of 1.5 and above represents the top 10% of the overall distribution.
FIG. 7.
FIG. 7.
Correlation plot between scoring method 1 and geometric mean IC50 titers. Each data point represents the geometric mean IC50 titer of all 463 samples tested on panel 3 against all 15 pseudoviruses evaluated. Samples that were scored between 1.5 and 2 had an average IC50 titer of 1:100 to 1:300. Samples that were scored between 2 and 2.4 had an average IC50 titer between 1:300 and 1:500. Samples with scores greater than or equal to 2.5 have an average IC50 titer greater than 1:500.
FIG. 8.
FIG. 8.
Distribution of neutralization sensitivities of early/chronic HIV-1 Env clones on panel 3 among the top 5% of samples from HIV-1-infected individuals screened on panel 1. Each bar represents the geometric mean IC50 titer of 26 serum and plasma samples from Rwanda, Zambia, Uganda, Australia, and the United Kingdom.
FIG. 9.
FIG. 9.
Proportion of elite neutralizers with neutralization scores of ≥2.5 by site. Percentages represent the top 1% (n = 18) of 1,798 samples screened on panels 1, 2, 3, and 4.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Binley, J. M., E. A. Lybarger, E. T. Crooks, M. S. Seaman, E. Gray, K. L. Davis, J. M. Decker, D. Wycuff, L. Harris, N. Hawkins, B. Wood, C. Nathe, D. Richman, G. D. Tomaras, F. Bibollet-Ruche, J. E. Robinson, L. Morris, G. M. Shaw, D. C. Montefiori, and J. R. Mascola. 2008. Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. J. Virol. 8211651-11668. - PMC - PubMed
    1. Binley, J. M., T. Wrin, B. Korber, M. B. Zwick, M. Wang, C. Chappey, G. Stiegler, R. Kunert, S. Zolla-Pazner, H. Katinger, C. J. Petropoulos, and D. R. Burton. 2004. Comprehensive cross-clade neutralization analysis of a panel of anti-human immunodeficiency virus type 1 monoclonal antibodies. J. Virol. 7813232-13252. - PMC - PubMed
    1. Burton, D. R. 1997. A vaccine for HIV type 1: the antibody perspective. Proc. Natl. Acad. Sci. USA 9410018-10023. - PMC - PubMed
    1. Burton, D. R., and C. F. Barbas III. 1994. Human antibodies from combinatorial libraries. Adv. Immunol. 57191-280. - PubMed
    1. Burton, D. R., C. F. Barbas III, M. A. Persson, S. Koenig, R. M. Chanock, and R. A. Lerner. 1991. A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc. Natl. Acad. Sci. USA 8810134-10137. - PMC - PubMed

Publication types

MeSH terms