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
. 2012 Nov;18(11):1688-92.
doi: 10.1038/nm.2985. Epub 2012 Oct 21.

Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape

Penny L Moore  1 , Elin S Gray, C Kurt Wibmer, Jinal N Bhiman, Molati Nonyane, Daniel J Sheward, Tandile Hermanus, Shringkhala Bajimaya, Nancy L Tumba, Melissa-Rose Abrahams, Bronwen E Lambson, Nthabeleng Ranchobe, Lihua Ping, Nobubelo Ngandu, Quarraisha Abdool Karim, Salim S Abdool Karim, Ronald I Swanstrom, Michael S Seaman, Carolyn Williamson, Lynn Morris
Affiliations

Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape

Penny L Moore et al. Nat Med. 2012 Nov.

Abstract

Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1-infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Characterizing the antibody specificities and viral populations in CAP177 and CAP314. (a) Serial plasma neutralization of three heterologous viruses (Q23, Du156 and TRO.11 for CAP177 and Q23, Du156 and CAP200 for CAP314) compared to mutant viruses where the 332 glycan was deleted by mutagenesis. Wild-type viruses are shown in orange and mutants in blue. (b) Sequence alignment showing part of the C3 region from 2 weeks (CAP177) or 3 months (CAP314) up to 28–30 months after infection. The number of sequences at each time point is indicated. Gray shading indicates the presence of a predicted N-linked glycan, and dashes indicate sequence identity compared to the acute sequence. HXB2 numbering is used throughout. (c) The frequency of the 332 glycan is shown over time (as pie charts) relative to neutralization of the acute autologous virus (corresponding to the 2-week and 3-month sequences shown above, gray line) and sensitive heterologous viruses (of subtype C in orange, subtype B in blue and subtype A in green). Plasma samples were available only up to 2 years after infection for CAP314, who received antiretroviral therapy shortly thereafter.
Figure 2
Figure 2
The glycan at position 332 mediates neutralization escape in CAP177 and CAP314. (a) Partial sequence alignment showing the CAP177 acute virus (CAP177 2 weeks), a representative 6-month clone (CAP177 6 months) and the acute virus mutated to contain a glycan at position 332, which deletes the glycan at position 334 (CAP177 2 weeks N334S). All three clones were tested for neutralization sensitivity to autologous serum from 6 months after infection. (b) Partial sequence alignment showing the CAP314 acute virus (CAP314 3 months), a representative 6-month clone (CAP314 6 months) and the mutated virus (CAP314 3 months N334S) and their sensitivity to autologous serum from 6 months after infection. Residual neutralization of the CAP314 3 months N334S mutant reflects the presence of neutralizing antibody specificities targeting other epitopes, as described previously. Experiments were performed three times, and error bars represent the s.e.m.
Figure 3
Figure 3
The glycan at residue 332 is underrepresented in subtype C transmitted/founder viruses, which are also frequently resistant to the PGT128 mAb. (a) Comparison of the frequency of the 332 glycan among 1,371 envelope sequences from 68 subjects with HIV-1 subtype C acute or early infection and 1,111 sequences from 62 subjects with chronic HIV-1 subtype C infections (L.P., S. Joseph, J. Anderson, M.-R.A., J. Salazar-Gonzalez et al., unpublished data). We also analyzed a smaller data set of matched sequences (502 sequences from 20 subjects from the CAPRISA cohort), and compared acute sequences to those from the same individual at 1 year after infection. For subtype B, a published data set of 2,715 acute sequences from 88 subjects and 2,122 sequences from 86 chronic infections was used. (b) Neutralization sensitivity of 101 transmitted/founder viruses to neutralization by the PGT128 mAb. (c) Neutralization sensitivity of subtype C transmitted/founder viruses correlated strongly with the presence or absence of the 332 glycan. Colors reflect neutralization IC50 titers >10 μg ml−1 (blue), 1–10 μg ml−1 (yellow), 0.1–1μg ml−1 (orange) and <0.1 μg ml−1 (red).
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Haynes BF, Montefiori DC. Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates. Expert Rev. Vaccines. 2006;5:347–363. - PMC - PubMed
    1. Hu SL, Stamatatos L. Prospects of HIV Env modification as an approach to HIV vaccine design. Curr. HIV Res. 2007;5:507–513. - PubMed
    1. Phogat S, Wyatt R. Rational modifications of HIV-1 envelope glycoproteins for immunogen design. Curr. Pharm. Des. 2007;13:213–227. - PubMed
    1. Li Y, et al. Analysis of neutralization specificities in polyclonal sera derived from human immunodeficiency virus type 1–infected individuals. J. Virol. 2009;83:1045–1059. - PMC - PubMed
    1. Sather DN, et al. Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J. Virol. 2009;83:757–769. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources