Reconstruction of a polyclonal ADCC antibody repertoire from an HIV-1 non-transmitting mother

Zak A Yaffe; Shilei Ding; Kevin Sung; Vrasha Chohan; Lorie Marchitto; Laura Doepker; Duncan Ralph; Ruth Nduati; Frederick A Matsen 4th; Andrés Finzi; Julie Overbaugh

doi:10.1016/j.isci.2023.106762

Reconstruction of a polyclonal ADCC antibody repertoire from an HIV-1 non-transmitting mother

iScience. 2023 Apr 26;26(5):106762. doi: 10.1016/j.isci.2023.106762. eCollection 2023 May 19.

Authors

Zak A Yaffe^{1

2

3}, Shilei Ding⁴, Kevin Sung⁵, Vrasha Chohan¹, Lorie Marchitto^{4

6}, Laura Doepker¹, Duncan Ralph⁵, Ruth Nduati⁷, Frederick A Matsen 4th^{5

8}, Andrés Finzi^{4

6}, Julie Overbaugh^{1

5}

Affiliations

¹ Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
² Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
³ Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.
⁴ Centre de Recherche du CHUM (CRCHUM), Montréal, QC H2X 0A9, Canada.
⁵ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
⁶ Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H2X 0A9, Canada.
⁷ Department of Paediatrics and Child Health, University of Nairobi, Kenyatta National Hospital, Nairobi, Kenya.
⁸ Howard Hughes Medical Institute, Seattle, WA 98109, USA.

Abstract

Human natural history and vaccine studies support a protective role of antibody dependent cellular cytotoxicity (ADCC) activity against many infectious diseases. One setting where this has consistently been observed is in HIV-1 vertical transmission, where passively acquired ADCC activity in HIV-exposed infants has correlated with reduced acquisition risk and reduced pathogenesis in HIV+ infants. However, the characteristics of HIV-specific antibodies comprising a maternal plasma ADCC response are not well understood. Here, we reconstructed monoclonal antibodies (mAbs) from memory B cells from late pregnancy in mother MG540, who did not transmit HIV to her infant despite several high-risk factors. Twenty mAbs representing 14 clonal families were reconstructed, which mediated ADCC and recognized multiple HIV Envelope epitopes. In experiments using Fc-defective variants, only combinations of several mAbs accounted for the majority of plasma ADCC of MG540 and her infant. We present these mAbs as evidence of a polyclonal repertoire with potent HIV-directed ADCC activity.

Keywords: Immunology; Pediatrics; Virology.

Abstract

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