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

Mathieu Claireaux,Xian Tang,Rémy Robinot,Mélanie Héry,Alexandre Nouël,Jérôme Kervevan,Christiane Bouchier,David Zucman,Olivier Schwartz,Julian Buchrieser,Isabelle Staropoli,Mandar Patgaonkar,Samia Hendou,Émeline Perthame ,Pierre De Truchis,Laurence Ma,Olivier Lambotte,Faroudy Boufassa,Stacy Gellenoncourt,Anne Brelot,Milena Hasan,Thomas Cokelaer,Stevenn Volant,Valentina Libri,Véronique Avettand-Fènoël ,Lisa A Chakrabarti

doi:10.1038/s41467-022-28130-0

Abstract

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.

Highlights

HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions
Gag[293] can be presented by multiple HLA II alleles[17], which enabled the recruitment of patients with expressing at least one of 7 HLA DRB1 alleles (Supplementary Table 1)
Each Peripheral blood mononuclear cells (PBMC) sample was labeled in parallel with a Gag293-loaded MHCII tetramer and a control tetramer loaded with the CLIP peptide

Summary

Introduction

HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. CD4 + T cells from controllers maintain high proliferative capacity in response to HIV antigens and show only limited expression of immune exhaustion markers[11] Effector functions such as polyfunctional cytokine secretion and help provided to B cells appear superior in HIV controllers compared to other patients groups[12,13,14]. In the absence of strong genetic associations, the factors responsible for the preservation of high-affinity CD4 + T cells in HIV controllers remain to be elucidated To address this issue, we set to compare the differentiation and activation status of Gag293-specific CD4 + T cells obtained from HIV controllers and long-term treated patients. Genetic and TCR-dependent regulation of the CCR5 pathway provides a mechanistic explanation for the preservation of the specific CD4 + T cell population in HIV controller patients

Methods

Results

Conclusion