Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8+ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4+ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8+ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.

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BackgroundIntact LINE-1 elements are the only retrotransposons encoded by the human genome known to be capable of autonomous replication. Numerous cases of genetic disease have been traced to gene disruptions caused by LINE-1 retrotransposition events in germ-line cells. In addition, genomic instability resulting from LINE-1 retrotransposition in somatic cells has been proposed as a contributing factor to oncogenesis and to cancer progression. LINE-1 element activity may also play a role in normal physiology.Methods and Principal FindingsUsing an in vitro LINE-1 retrotransposition reporter assay, we evaluated the abilities of several antiretroviral compounds to inhibit LINE-1 retrotransposition. The nucleoside analogue reverse transcriptase inhibitors (nRTIs): stavudine, zidovudine, tenofovir disoproxil fumarate, and lamivudine all inhibited LINE-1 retrotransposition with varying degrees of potencies, while the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine showed no effect.Conclusions/SignificanceOur data demonstrates the ability for nRTIs to suppress LINE-1 retrotransposition. This is immediately applicable to studies aimed at examining potential roles for LINE-1 retrotransposition in physiological processes. In addition, our data raises novel safety considerations for nRTIs based on their potential to disrupt physiological processes involving LINE-1 retrotransposition.

BackgroundThe effect of alternative spontaneous breathing trial (SBT) techniques on extubation success and other clinically important outcomes is uncertain.MethodsWe searched MEDLINE, EMBASE, CENTRAL, CINAHL, Evidence-Based Medicine Reviews, Ovid Health Star, proceedings of five conferences (1990–2016), and reference lists for randomized trials comparing SBT techniques in intubated adults or children. Primary outcomes were initial SBT success, extubation success, or reintubation. Two reviewers independently screened citations, assessed trial quality, and abstracted data.ResultsWe identified 31 trials (n = 3541 patients). Moderate-quality evidence showed that patients undergoing pressure support (PS) compared with T-piece SBTs (nine trials, n = 1901) were as likely to pass an initial SBT (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.89–1.11; I 2 = 77%) but more likely to be ultimately extubated successfully (RR 1.06, 95% CI 1.02–1.10; 11 trials, n = 1904; I 2 = 0%). Exclusion of one trial with inconsistent results for SBT and extubation outcomes suggested that PS (vs T-piece) SBTs also improved initial SBT success (RR 1.06, 95% CI 1.01–1.12; I 2 = 0%). Limited data suggest that automatic tube compensation plus continuous positive airway pressure (CPAP) vs CPAP alone or PS increase SBT but not extubation success.ConclusionsPatients undergoing PS (vs T-piece) SBTs appear to be 6% (95% CI 2–10%) more likely to be extubated successfully and, if the results of an outlier trial are excluded, 6% (95% CI 1–12%) more likely to pass an SBT. Future trials should investigate patients for whom SBT and extubation outcomes are uncertain and compare techniques that maximize differences in support.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1698-x) contains supplementary material, which is available to authorized users.