Impaired Immune Reconstitution in HIV Infection: the Role of CD4+ T-Cell-Associated NKG2D Ligands, CD4+ T-Cell Subsets Imbalance, and Immune Function Deficiency

Qianqian Xu ¹ Qiuyue Zhang ² Peng Xu ¹ Tong Zhang ¹ Hao Wu ¹ XIN ZHANG ^1* Christiane Moog ^3* Bin Su ^1*

• ¹ Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
• ² Department of Immunity and Infectious Diseases, Third People's Hospital of Shenzhen, National Clinical Research Center for Infectious Diseases, Shenzhen, China
• ³ Laboratoire d’ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, Alsace, France

Objective: This study mainly focuses on the profiles of cell receptors and their relative ligands for NK cells and CD4+ T cells exhibited on INRs and immunological responders (IRs) in order to analyze the impact of differential immune status on immune reconstitution in PLWH receiving ART.Methods: This study included 66 PLWH who had been on ART for 4 years, comprising 32 INRs and 34 IRs. Using flow cytometry, we examined the expression of cell receptors and ligands for NK cells and CD4+ T cells in PBMCs, as well as the differentiation of CD4+ T cells.Results: The expression of NKG2D ligands, including MICA/B and ULBP2-5, on CD4+ T cells in INRs is elevated prior to ART. Further research found that the expression of CD95 on MICA/B+CD4+ T cells and ULBP2-5+CD4+ T cells was higher in INRs before ART compared to IRs. Simultaneously, the percentages of death receptor CD95 expression on MICA/B+CD4+ T cells and on ULBP2-5+CD4+ T cells before ART were negatively correlated with CD4+ T-cell counts and ΔCD4. Among the CD4+ T-cell subsets, an imbalance persists in the CD4+ Tcm and CD4+ Temra subsets in both INRs and IRs, before or after ART. CD4+ T cells exhibit elevated levels of activation, proliferation, exhaustion, and apoptosis prior to ART initiation. However, CD4+ T-cell activation and proliferation normalize post-ART, while apoptosis and exhaustion levels remain significantly elevated. Regardless of ART, the anti-apoptotic capacity of CD4+ T cells in both INRs and IRs is still lower than that of healthy controls (HCs). Before ART, the frequency of CD31 expression on naive CD4+ T cells in INRs is lower than that in IRs and HCs. Following ART, the amounts of CD31+ Tn from CD4+ T cells remain impaired in both INRs and IRs compared to HCs.Conclusion: The upregulation of related ligands for NKG2D receptor on CD4+ T cells in INRs is associated with increased susceptibility of CD4+ T cells to NK cell-mediated killing. The imbalance in CD4+ Tcm and CD4+ Temra subset homeostasis and impaired CD31 expression on naive CD4+ T cells in INRs are associated with poor immune reconstitution outcomes.