201. HIV broadly neutralizing antibodies and immunological tolerance (VAC7P.988)
- Author
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Guang Yang, Mengfei Liu, Kevin Wiehe, Nathan Nicely, Barton Haynes, John Mascola, Pamela Bjorkman, and Garnett Kelsoe
- Subjects
Immunology ,Immunology and Allergy - Abstract
It is generally thought that many human antibodies (Ab) that neutralize multiple clades of HIV-1 (bnAbs) are self-reactive. We previously identified kynureninase as the primary self-antigen recognized by 2F5, suggesting that generation of Ab to the 2F5 epitope of HIV-1 may be proscribed by immune tolerance, a notion supported by impaired B-cell development in mice expressing the 2F5 VH and VL regions. However, there is a lack of quantitative and systemic assessment of polyreactivity among HIV bnAbs. In addition, it is unknown whether other classes of HIV-1 bnAbs and non-neutralizing antibodies are also influenced by immunological tolerance. Here, we used protein microarrays to assess bnAb binding to over 9,600 human proteins and compared bnAb binding profiles to HIV non-neutralizing antibodies. We found that bnAbs as a class are more autoreactive and more polyreactive than non-neutralizers. Interestingly, 4 of 7 CD4bs bnAbs screened from 2 distinct lineages (VRC01, VRC02, CH103 and CH106) bind human protein ubiquitin ligase E3A (UBE3A). We confirmed this crossreactivity in ELISA, and demonstrated that UBE3A competitively inhibits gp120 binding to VRC01. Our results demonstrate that HIV-1 bnAbs are significantly more polyreactive and self-reactive than non-neutralizers, which may subject them to immunological tolerance control in vivo. Our identification of UBE3A as a self-antigen of bnAbs provides a mechanism for the rarity and delayed development of certain CD4bs bnAbs.
- Published
- 2014