Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy

Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.

Suboptimal Immune Recovery Despite Sustained HIV Suppression Among a Yi Ethnic Population in Southwest China

Objectives: Despite sustained viral suppression with effective antiretroviral therapy (ART), HIV-infected patients with suboptimal immune recovery are still at high risk of non-AIDS-related and AIDS-related events. The aim of this study was to investigate the potential determinants associated with suboptimal CD4+ T cell count recovery during free ART with sustained viral suppression among a HIV-infected Yi ethnic population in Liangshan Prefecture, an area with high HIV prevalence in China.Method: This retrospective study included all HIV-infected Yi adults (≥ 18 years and with baseline CD4+ T cell count less than 500 cells/μL) who initiated ART supported by NFATP between January 2015 and December 2018 in Zhaojue county, Liangshan Prefecture (Figure 1), and achieved virological suppression (viral load < 50 copies/mL) within 12 months after ART initiation and maintained sustained virological suppression. Univariate and multivariate log-binomial regression models were used to assess determinants of suboptimal immune recovery, producing adjusted odds ratios (aORs) and confidence intervals (CIs).Results: A total of 277 HIV-infected Yi patients (male/female, 140/137) with a mean age of 36.57 ± 7.63 years and a mean baseline CD4+ T cell count of 284.49 ± 117.11 cells/μL were included. Nearly half of the Yi patients were infected through injection drug use (48.7%, 135/277), and the prevalence of anti-HCV antibody was high (43.7%, 121/277). The free ART regimens were 91% efavirenz-based, 5.1% nevirapine-based, and 3.9% lopinavir/ritonavir-based. After a mean 3.77 ± 1.21 years of ART, optimal immune recovery (CD4+ T cell count ≥ 500 cells/μL), intermediate immune recovery (350≤CD4 < 500 cells/μL), and suboptimal immune recovery (CD4 < 350 cells/μL) occurred in 32.9%, 31%, and 36.2% of the included patients, respectively. After adjustments, multivariable analysis revealed that low pre-ART CD4+ cell count, WHO clinical stage III and IV, and coinfection with HCV were associated with suboptimal immune recovery. Conclusions: Our study support prompt ART initiation after HIV diagnosis, and curative HCV treatment in HCV/HIV co-infected patients for improving the immunological effectiveness of ART among HIV-infected Yi patients in Liangshan Prefecture.Trial registration: None