Shielding design of an underground experimental area at point 5 of the CERN Super Proton Synchrotron (SPS)

Increasing projected values of the circulating beam intensity in the Super Proton Synchrotron (SPS) and decreasing limits to radiation exposure, taken with the increasing non-acceptance of unjustified and unoptimised radiation exposures, have led to the need to re-assess the shielding between the ECX and ECA5 underground experimental areas of the SPS. Twenty years ago, these experimental areas at SPS-Point 5 housed the UA1 experiment, where Carlo Rubbia and his team verified the existence of W and Z bosons. The study reported here describes such a re-assessment based on simulations using the multi-purpose FLUKA radiation transport code. This study concludes that while the main shield which is made of concrete blocks and is 4.8 m thick satisfactorily meets the current design limits even at the highest intensities presently planned for the SPS, dose rates calculated for liaison areas on both sides of the main shield significantly exceed the design limits. Possible ways of improving the shielding situation are discusse

Conference highlights of the 5th international workshop on HIV persistence during therapy, 6-9 December 2011, St. Maartin, West Indies

The December 2011 5th International Workshop on HIV Persistence during Therapy addressed the issue of HIV persistence among 210 scientists from 10 countries involved in the study of HIV reservoirs and the search of an HIV cure. High quality abstracts were selected and discussed as oral or poster presentations. The aim of this review is to distribute the scientific highlights of this workshop outside the group as analyzed and represented by experts in retrovirology, immunology and clinical research

Expression of the T4 molecule (AIDS virus receptor) by human brain-derived cells

AbstractThree human cell lines of astrocytic origin were evaluated for expression of a human T-lymphocyte surface glycoprotein, T4, which also serves as a cellular receptor for the human immunodeficiency virus (AIDS virus, HIV). T4 antigen was detected on the cell surface of 2 of these cell lines using monoclonal OKT-4 antibody and flow cytometry. Gene transcripts encoding the T4 molecule were detected by a ribonuclease protection assay in surface T4-positive and -negative cells. Our results suggest that astrocytes may serve as targets for HIV infection in the brain

Alpha Interferon-Induced Antiretroviral Activities: Restriction of Viral Nucleic Acid Synthesis and Progeny Virion Production in Human Immunodeficiency Virus Type 1-Infected Monocytes

Alpha interferon (IFN-a) restricts multiple steps of the human immunodeficiency virus type 1 (HIV-i) life cycle. A well-described effect of IFN-a is in the modulation of viral nucleic acid synthesis. We demonstrate that IFN-α influences HIV-1 DNA synthesis principally by reducing the production of late products of reverse transcription. The magnitude of IFN-α-induced downregulation of HIV-1 DNA and/or progeny virion production was dependent on the IFN-α concentration, the duration of cytokine administration, the multiplicity of infection, the viral strain, and the cycles of viral infection. Interestingly, reductions in viral DNAs could not fully account for the observed IFN-a-induced abrogation of progeny virion production. These data, by our investigation of both single-cycle and spreading viral infections, support a predominant but not exclusive effect of IFN-α on viral DNA synthesis

Apoptotic Killing of HIV-1–Infected Macrophages Is Subverted by the Viral Envelope Glycoprotein

Viruses have evolved strategies to protect infected cells from apoptotic clearance. We present evidence that HIV-1 possesses a mechanism to protect infected macrophages from the apoptotic effects of the death ligand TRAIL (tumor necrosis factor–related apoptosis-inducing ligand). In HIV-1–infected macrophages, the viral envelope protein induced macrophage colony-stimulating factor (M-CSF). This pro-survival cytokine downregulated the TRAIL receptor TRAIL-R1/DR4 and upregulated the anti-apoptotic genes Bfl-1 and Mcl-1. Inhibition of M-CSF activity or silencing of Bfl-1 and Mcl-1 rendered infected macrophages highly susceptible to TRAIL. The anti-cancer agent Imatinib inhibited M-CSF receptor activation and restored the apoptotic sensitivity of HIV-1–infected macrophages, suggesting a novel strategy to curtail viral persistence in the macrophage reservoir

Modulating HIV-1 replication by RNA interference directed against human transcription elongation factor SPT5

BACKGROUND: Several cellular positive and negative elongation factors are involved in regulating RNA polymerase II processivity during transcription elongation in human cells. In recruiting several of these regulatory factors to the 5' long terminal repeat (LTR) promoter during transcription elongation, HIV-1 modulates replication of its genome in a process mediated by the virus-encoded transactivator Tat. One particular cellular regulatory factor, DSIF subunit human SPT5 (hSpt5), has been implicated in both positively and negatively regulating transcriptional elongation but its role in Tat transactivation in vivo and in HIV-1 replication has not been completely elucidated. RESULTS: To understand the in vivo function of hSpt5 and define its role in Tat transactivation and HIV-1 replication, we used RNA interference (RNAi) to specifically knockdown hSpt5 expression by degrading hSpt5 mRNA. Short-interfering RNA (siRNA) designed to target hSpt5 for RNAi successfully resulted in knockdown of both hSpt5 mRNA and protein levels, and did not significantly affect cell viability. In contrast to hSpt5 knockdown, siRNA-mediated silencing of human mRNA capping enzyme, a functionally important hSpt5-interacting cellular protein, was lethal and showed a significant increase in cell death over the course of the knockdown experiment. In addition, hSpt5 knockdown led to significant decreases in Tat transactivation and inhibited HIV-1 replication, indicating that hSpt5 was required for mediating Tat transactivation and HIV-1 replication. CONCLUSIONS: The findings presented here showed that hSpt5 is a bona fide positive regulator of Tat transactivation and HIV-1 replication in vivo. These results also suggest that hSpt5 function in transcription regulation and mRNA capping is essential for a subset of cellular and viral genes and may not be required for global gene expression

Episomal Viral cDNAs Identify a Reservoir That Fuels Viral Rebound after Treatment Interruption and That Contributes to Treatment Failure

Viral reservoirs that persist in HIV-1 infected individuals on antiretroviral therapy (ART) are the major obstacle to viral eradication. The identification and definition of viral reservoirs in patients on ART is needed in order to understand viral persistence and achieve the goal of viral eradication. We examined whether analysis of episomal HIV-1 genomes provided the means to characterize virus that persists during ART and whether it could reveal the virus that contributes to treatment failure in patients on ART. For six individuals in which virus replication was highly suppressed for at least 20 months, proviral and episomal genomes present just prior to rebound were phylogenetically compared to RNA genomes of rebounding virus after therapy interruption. Episomal envelope sequences, but not proviral envelope sequences, were highly similar to sequences in rebounding virus. Since episomes are products of recent infections, the phylogenetic relationships support the conclusion that viral rebound originated from a cryptic viral reservoir. To evaluate whether the reservoir revealed by episomal sequence analysis was of clinical relevance, we examined whether episomal sequences define a viral population that contributes to virologic failure in individuals receiving the CCR5 antagonist, Vicriviroc. Episomal envelope sequences at or near baseline predicted treatment failure due to the presence of X4 or D/M (dual/mixed) viral variants. In patients that did not harbor X4 or D/M viruses, the basis for Vicriviroc treatment failure was indeterminate. Although these samples were obtained from viremic patients, the assay would be applicable to a large percentage of aviremic patients, based on previous studies. Summarily, the results support the use of episomal HIV-1 as an additional or alternative approach to traditional assays to characterize virus that is maintained during long-term, suppressive ART