Characteristics And Immune-regulatory Mechanisms Of B Cell CD39/CD73/Adenosine Pathway In Patients With Chronic HIV-1 Infection

Background:Adenosine(ADO)is an effective immunomodulator,mainly produced by hydrolysis of ATP through two extracellular nucleotide enzymes(CD39 and CD73).ADO and its receptors participate in the regulation of cellular immune response and play an important role in the development of various diseases.Several studies confirmed that the expression of CD39 or CD73 on T cells in patients with human immunodeficiency virus(HIV)-1 infection were closely associated with the progression and prognosis of acquired immune deficiency syndrome(AIDS)disease.In addition,CD39 and CD73,constitutively expressed on B cells,regulate T and B cell responses through ADO.However,the characteristics and mechanisms of CD39/CD73/adenosine pathway in chronic HIV-1 infection remains elusive.Objective:The purpose of this study was to investigate the characteristics of B cell CD39/CD73/adenosine pathway in chronic HIV-1 infection and its impact on the progression of HIV-1/AIDS.Methods:One hundred and thirty-six chronic HIV-1 infected patients,including 100typical progressors(TPs)and 36 complete responders(CRs),were recruited for this study,meanwhile,36 age-and sex-matched healthy individuals were enrolled as health controls(HCs).(1)We used flow cytometry and immunofunctional assays to detect the expression of CD39 and CD73 on B cell in patients with chronic HIV-1 infection,and analyzed its correlation with disease progression of AIDS.(2)We used ELISA method to detect the plasma levels of soluble CD14(sCD14)and intestinal fatty acid-binding protein(I-FABP),and analyzed their correlations with the frequencies of CD39~+,CD73~+and CD39~+CD73~+B cells in patients with chronic HIV-1 infection.(3)The capacity of B cells from patients with chronic HIV-1 infection and HCs to metabolize ATP into ADO was detected by mass spectrometry in vitro.(4)The effect of exogenous ADO on apoptosis and proliferation of T cells were analyzed in vitro,and the influence of exogenous ADO on HIV-1 virus production was explored using J-lat cell line in vitro.Results:CD39 and CD73 expression on total B cells and their subsets were progressively decreased in treatment-naive HIV-1-infected patients,and directly correlated with disease progression,as indicated by markers for disease progression(CD4 counts and viral load),immune balance(CD4/CD8 ratio),T cells activation(CD38),monocyte activation(sCD14),and intestinal mucosal damage(I-FABP).B cells in the presence of X4 HIV-1 isolates upregulated CD39 but downregulated CD73expression.Importantly,B cells in AIDS patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular ADO.In response to ADO,monocytes from AIDS patients showed a decreased level of activation,and their T cells exhibited increased apoptosis,decreased proliferation,and reduced HIV-1 virus production.Conclusions:These data indicated that the skewed CD39 and CD73 expression on B cells,as well as their decreased ADO production,are closely associated with disease progression in patients with chronic HIV-1 infection.These findings not only extend our understanding of B cell pathology in HIV-1 infection but also support the notion that modifying the ADO pathway might be an attractive approach to treat patients with HIV-1 infection.