TCR-mimic bispecific antibodies to target the HIV-1 reservoir

Srona Sengupta, Nathan L. Board, Fengting Wu, Milica Moskovljevic, Jacqueline Douglass, Josephine Zhang, Bruce R. Reinhold, Jonathan Duke-Cohan, Jeanna Yu, Madison C. Reed, Yasmine Tabdili, Aitana Azurmendi, Emily J. Fray, Hao Zhang, Emily Han Chung Hsiue, Katharine Jenike, Ya Chi Ho, Sandra B. Gabelli, Kenneth W. Kinzler, Bert VogelsteinShibin Zhou, Janet D. Siliciano, Scheherazade Sadegh-Nasseri, Ellis L. Reinherz, Robert F. Siliciano

Research output: Contribution to journalArticlepeer-review

Abstract

HIV-1 infection is incurable due to the persistence of the virus in a latent reservoir of resting memory CD4+ T cells. “Shock-and-kill” approaches that seek to induce HIV-1 gene expression, protein production, and subsequent targeting by the host immune system have been unsuccessful due to a lack of effective latency-reversing agents (LRAs) and kill strategies. In an effort to develop reagents that could be used to promote killing of infected cells, we constructed T cell receptor (TCR)-mimic antibodies to HIV-1 peptide-major histocompatibility complexes (pMHC). Using phage display, we panned for phages expressing antibody-like variable sequences that bound HIV-1 pMHC generated using the common HLA-A*02:01 allele. We targeted three epitopes in Gag and reverse transcriptase identified and quantified via Poisson detection mass spectrometry from cells infected in vitro with a pseudotyped HIV-1 reporter virus (NL4.3 dEnv). Sequences isolated from phages that bound these pMHC were cloned into a single-chain diabody backbone (scDb) sequence, such that one fragment is specific for an HIV-1 pMHC and the other fragment binds to CD3ε, an essential signal transduction subunit of the TCR. Thus, these antibodies utilize the sensitivity of T cell signaling as readouts for antigen processing and as agents to promote killing of infected cells. Notably, these scDbs are exquisitely sensitive and specific for the peptide portion of the pMHC. Most importantly, one scDb caused killing of infected cells presenting a naturally processed target pMHC. This work lays the foundation for a novel therapeutic killing strategy toward elimination of the HIV-1 reservoir.

Original languageEnglish (US)
Article numbere2123406119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number15
DOIs
StatePublished - Apr 12 2022

Keywords

  • HIV-1
  • antigen processing
  • human leukocyte antigen
  • immunotherapy
  • latent reservoir

ASJC Scopus subject areas

  • General

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