Immune Activation In Chronic HIV Infection And Effect Of Extracts Of A Chinese Medical Plant On Immune Activation Among ART-Treated, Immunological Nonresponders

[Objective]:Human immunodeficiency virus (HIV) infection is associated with persistent immune activation which has been shown to be a predictor of disease progression. Approximately20%of HIV-infected adults do not normalize their CD4+T cell counts after long-term effective combined antiretroviral therapy (ART), who are defined as immunological nonresponders (INR). INR are associated with high level of immune activation. This study analyzed the association between CD38or HLA-DR expression on peripheral blood CD8+T cells and disease progression in treatement-naive adult Chinese HIV patients. The association between CD8+T cell activation status and responses to ART in adult HIV patients were studied. The effects of extracts of a Chinese medical plant (Tripterygium wilfordii Hook F, TwHF) on immune activation in INR patients were evaluated.[Methods]:1. Crosssectional study:Four hundred and seventy-one ART-naive HIV-infected patients were included. CD38and HLA-DR expression on peripheral blood CD8+T cells, CD4+T cell count, memory and naive CD4+T cell subsets were measured by flow cytometry. Plasma HIV-RNA was dtermined by branched DNA approach.2. Cohort study:CD38and HLA-DR expression on peripheral blood CD8+T cells was longitudinally assessed in162HIV-infected patients who underwent ART. Patients were followed at baseline, one month after ART initiation and at a3-month intevals thereafter.3. Prospective study:Eleven HIV-infected INRs (CD4count<300cells/μl or CD4increase<20%in the last12months with suppressive ART) were enrolled in a12-month pilot study. Extracts of TwHF (10mg,3times daily) were added to the background ART for one year. Subjects were followed at prior to TwHF therapy and at12,24,36, and48weeks after therapy.[Results]:1. Crosssectional study:CD38expression levels on peripheral blood CD8+T cells negatively correlated with CD4+T cell count (r=-0.53, p<0.0001) and naive CD4+T cell count (r=-0.48,p<0.0001). CD38expression on CD8+T cells also displayed significantly negative correlation with CD28expression on CD8+T cells (r=-0.46,p<0.0001). HLA-DR expression on CD8+T cells had no significant correlation with CD4+T cell count. CD8+T cell activaton levels were similar among the different transmission groups. No correlation was found between CD8+T cell activaton and duration of infection.2. Cohort study:The median viral load was decreased from4.65log10copies/ml at baseline to1.69log10copies/ml at month12. CD4counts steadily increased over the course of treatment. The median CD4count went up from121/μl at baseline to270/μl at12months of therapy. Memory and naive CD4subsets increased111/μl and48/μl respectively. Expression of both activaton markers on CD8+T cells decreased significantly (HLA-DR from44.1%at baseline to31.0%at month12, CD38from77.2%at baseline to43.5%at month12). Negative correlation was found between CD38expression on CD8+T cells and CD4count beyond the first year of the suppressive ART.3. Prospective study:Extracts of TwHF had a notable impact on immune activation as shown by significant decrease of the following parameters: HLA-DR-CD38+CD8+/CD8+, HLA-DR+CD38+CD8+/CD8+, HLA-DR-CD38+CD4+/CD4+, HLA-DR+CD38+CD4+/CD4+. TwHF-induced immune modulation was associated with increased percentage and count of circulating CD4+T cells.[Conclusion]:Compared with HLA-DR expression on CD8+T cells, CD38expression shows stronger association with CD4+T cell count in treatment-naive patients. Transmission and duration of infection probably have no impact on CD8+T cell activation levels. CD38expression on CD8+T cells negatively correlates with CD4count under long-term suppressive ART. Patients treated with low-dose TwHF combined with background ART display significantly decreased immune activation and increased CD4recovery. Further randomized control trials are required to assess the efficacy of TwHF in treating INR.