Acute caffeine ingestion affects surround suppression of perceived contrast.

Caffeine is a widely used psychostimulant that is associated with increased acetylcholine levels in mammalian brain and acetycholinesterase antagonism. Acetylcholine, a neuromodulator, plays an important role in the processing of visual information. One key example in human vision, thought to at least partly involve cholinergic neuromodulation, is perceptual surround suppression of contrast, whereby the perceived contrast of a pattern is altered by the presence of a neighbouring pattern. Perceptual surround suppression is weaker with pharmacological administration of donepezil (a centrally-acting acetylcholine enzyme inhibitor) in healthy human observers. Here, we test whether temporarily manipulating caffeine levels (from complete washout to a controlled dose of caffeine) has a similar effect on perceptual surround suppression in 21 healthy young adults (aged 20-24 years, 11 females). Neither ingestion of a caffeine pill nor placebo altered contrast judgments when the target pattern was presented on a uniform grey background ( p=0.54). With caffeine ingestion, perceptual surround suppression strength was reduced relative to baseline (prior to pill ingestion, p=0.003) and placebo ( p=0.029), irrespective of whether the surround was oriented parallel or orthogonal to the central target. While daily habitual caffeine consumption of low-to-moderate doses (<400 mg/day, estimated from a written questionnaire) is not predictive of performance, our study indicates that acute consumption of caffeine on the day of testing influences perceptual surround suppression strength. Perceptual surround suppression is predominantly attributed to inhibitory processes involving the major cortical inhibitory neurotransmitter, gamma-aminobutyric acid. Our results point to the involvement of other neuromodulators, possibly cholinergic, in perceptual surround suppression.

HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates.

The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics.

Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.

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.

Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition.

BACKGROUND: Intact 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 FINDINGS: Using 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/SIGNIFICANCE: Our 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.