ABSTRACT
Early antiretroviral therapy (ART) in HIV-infected infants generally fails to achieve a sustained state of ART-free virologic remission, even after years of treatment. Our studies show that viral reservoir seeding is different in neonatal macaques intravenously exposed to SIV at birth, in contrast to adults. Furthermore, one month of ART including an integrase inhibitor, initiated at day 3, but not day 4 or 5 post infection, efficiently and rapidly suppresses viremia to undetectable levels. Intervention initiated at day 3 post infection and continued for 9 months achieves a sustained virologic remission in 4 of 5 infants. Collectively, an early intervention strategy within a key timeframe and regimen may result in viral remission or successful post-exposure prophylaxis for neonatal SIV infection, which may be clinically relevant for optimizing treatment strategies for HIV-infected or exposed infants.
Subject(s)
HIV Infections , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Anti-Retroviral Agents/therapeutic use , HIV Infections/drug therapy , HIV Infections/prevention & control , Humans , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/drug therapy , Viral Load , Viremia/drug therapyABSTRACT
High tissue iron levels are a risk factor for multiple chronic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). To investigate causal relationships and underlying mechanisms, we used an established NAFLD model-mice fed a high fat diet with supplemental fructose in the water ("fast food", FF). Iron did not affect excess hepatic triglyceride accumulation in the mice on FF, and FF did not affect iron accumulation compared to normal chow. Mice on low iron are protected from worsening of markers for non-alcoholic steatohepatitis (NASH), including serum transaminases and fibrotic gene transcript levels. These occurred prior to the onset of significant insulin resistance or changes in adipokines. Transcriptome sequencing revealed the major effects of iron to be on signaling by the transforming growth factor beta (TGF-ß) pathway, a known mechanistic factor in NASH. High iron increased fibrotic gene expression in vitro, demonstrating that the effect of dietary iron on NASH is direct. Conclusion: A lower tissue iron level prevents accelerated progression of NAFLD to NASH, suggesting a possible therapeutic strategy in humans with the disease.
