CD4 downregulation precedes Env expression and protects HIV-1-infected cells from ADCC mediated by non-neutralizing antibodies
Antibody-dependent cellular cytotoxicity (ADCC) represents an effective immune response for clearing virally infected cells, making ADCC-mediating antibodies promising therapeutic candidates for HIV-1 cure strategies. Broadly neutralizing antibodies (bNAbs) target epitopes present on the native "closed" envelope glycoprotein (Env), while non-neutralizing antibodies (nnAbs) recognize epitopes exposed upon Env-CD4 interaction. Here, we provide evidence that <i>env</i> mRNA is predominantly expressed by productively infected cells that have already downmodulated cell-surface CD4. This indicates that CD4 downmodulation by HIV-1 precedes Env expression, making productively infected cells resistant to ADCC mediated by nnAbs but sensitive to those mediated by bnAbs. These findings offer critical insights for the development of immunotherapy-based strategies aimed at targeting and eliminating productively infected cells in people living with HIV.
Authors
- Mathieu Dubé (ORCID: https://orcid.org/0000-0002-5522-9019)
- Gérémy Sannier (ORCID: https://orcid.org/0000-0001-7956-4463)
- Jérémie Prévost (ORCID: https://orcid.org/0000-0002-5260-5154)
- Debashree Chatterjee (ORCID: https://orcid.org/0000-0003-0276-9262)
- Guillaume Beaudoin-Bussières (ORCID: https://orcid.org/0000-0002-8092-4101)
- Lorie Marchitto (ORCID: https://orcid.org/0000-0002-4367-0229)
- Jonathan Richard (ORCID: https://orcid.org/0000-0002-9015-9589)
- Hongil Kim (ORCID: https://orcid.org/0000-0002-5325-0295)
- Mehdi Benlarbi (ORCID: https://orcid.org/0000-0001-9966-3784)
- Daniel E. Kaufmann (ORCID: https://orcid.org/0000-0003-4467-136X)
- Beatrice H. Hahn (ORCID: https://orcid.org/0000-0002-9400-9887)
- Andrés Finzi (ORCID: https://orcid.org/0000-0002-4992-5288)
- Catherine Bourassa (ORCID: https://orcid.org/0000-0003-1805-8860)
- Frank Kirchhoff (ORCID: https://orcid.org/0000-0002-7052-2360)
- Priti Kumar (ORCID: https://orcid.org/0000-0002-6901-5601)
- Halima Medjahed
- Yaping Sun (ORCID: https://orcid.org/0000-0002-3476-7280)
- Li Zhu (ORCID: https://orcid.org/0000-0002-3631-1236)
- Gloria-Gabrielle Delgado
Institutions
- Scripps Research Institute (US)
- Universität Ulm (DE)
- Yale University (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- Université de Montréal (CA)
- University of Pennsylvania (US)
- University of Lausanne (CH)
Publication Details
- Journal
- mBio
- Published
- 2024-10-07
- DOI
- https://doi.org/10.1128/mbio.01827-24
- Citations
- 11
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.23
Funders
- International AIDS Vaccine Initiative
- amfAR, The Foundation for AIDS Research
- Tulane University
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- National Institute of Allergy and Infectious Diseases