3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-γ release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

Background Early ART and virological suppression may impact on evolving antibody responses to HIV-infection. We evaluated frequency and predictors of seronegativity in infants starting early ART. Methods HIV-antibody results were compared between two of three arms of the Children with HIV Early Antiretroviral Therapy (CHER) trial: HIV-infected infants aged <12 weeks with CD4 ≥25% randomised to early-limited ART for 96 weeks (ART-96W) or deferred ART until clinical/immunological progression (ART-Def). HIV-infection was diagnosed by DNA PCR and RNA >1000 copies/ml. ART started at median age 7 and 23 weeks respectively. Antibody was measured from all available stored samples, ART-96W (n=109) and ART-Def (n=75), at trial week 84 (median age 92 (IQR 90.6–93.4) weeks) using 3 assays: 4th generation EIA HIV-antigen/antibody combination; HIV-1/2 rapid-antibody test and quantitative anti-gp120 IgG ELISA. Findings More ART-96W were seronegative than ART-Def by EIA (46% versus 11%, p<0.0001) and rapid-antibody test (53% versus 14%, p<0.0001). Anti-gp120 IgG was lower in ART-96W versus ART-Def (median 230 (133–13,129) versus 6,870 (IQR 1,706–53,645)μg/μl). Starting ART between 12-24 versus 0-12 weeks increased odds of seropositivity 13.7-fold (95%CI 3.1-60.2). All children starting ART aged >24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG levels (coefficient=0.54, p<0.0001) and increased odds of seropositivity OR 1.58 (95%CI 1.1-2.3) adjusted for ART-initiation age. Interpretation Almost half children starting ART before aged 12 weeks were HIV-seronegative by at aged ∼2 years. HIV-antibody tests cannot be used to re-confirm HIV-diagnosis in children starting early-ART. Long-term consequences of seronegativity need further study. Funding Wellcome Trust, Medical Research Council, National Institutes of Health.

ObjectivesEarly treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants’ immune systems are more plastic and dynamic than older children’s or adults’, and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and restart.MethodsData from HIV-infected children enrolled the CHER trial, starting ART aged between 6 and 12 weeks, were used to explore the effect of ART on immune reconstitution. We used linear and non-linear regression and mixed-effects models to describe children’s CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART.ResultsEarly treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption.ConclusionEarly identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children’s CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children’s CD4 levels.

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