Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry

Mathieu Claireaux (1) , Rémy Robinot (1) , Jérôme Kervevan (1) , Mandar Patgaonkar (1) , Isabelle Staropoli (1) , Anne Brelot (1) , Alexandre Nouël (1) , Stacy Gellenoncourt (1) , Xian Tang (1) , Mélanie Héry (1) , Stevenn Volant (2) , Emeline Perthame (2) , Véronique Avettand-Fenoël (3, 4) , Julian Buchrieser (1) , Thomas Cokelaer (2, 5) , Christiane Bouchier (5) , Laurence Ma (5) , Faroudy Boufassa (6) , Samia Hendou (6) , Valentina Libri (7) , Milena Hasan (7) , David Zucman (8) , Pierre de Truchis (9) , Olivier Schwartz (1) , Olivier Lambotte (10, 11, 12) , Lisa A. Chakrabarti (1)

1 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
2 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
3 Laboratoire de Microbiologie Clinique [AP-HP Hôpital Necker-Enfants Malades]
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 Biomics (plateforme technologique)
6 CESP - Centre de recherche en épidémiologie et santé des populations
7 UTechS CB - Cytometrie et Biomarqueurs – Cytometry and Biomarkers
8 Hôpital Foch [Suresnes]
9 Hôpital Raymond Poincaré [AP-HP]
10 IMVA - U1184 - Immunologie des Maladies Virales et Autoimmunes
11 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
12 UP11 - Université Paris-Sud - Paris 11

HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of β-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control.

Domains: Virology

Mathieu Claireaux, Rémy Robinot, Jérôme Kervevan, Mandar Patgaonkar, Isabelle Staropoli, et al.. Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry. Nature Communications, 2022, 13 (1), pp.521. ⟨10.1038/s41467-022-28130-0⟩. ⟨pasteur-03654265⟩